2-178543909-C-T
Variant summary
Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4BP6
The NM_001267550.2(TTN):c.96235G>A(p.Asp32079Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000309 in 1,613,510 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D32079H) has been classified as Uncertain significance.
Frequency
Consequence
NM_001267550.2 missense
Scores
Clinical Significance
Conservation
Publications
Genome browser will be placed here
ACMG classification
Our verdict: Likely_benign. The variant received -2 ACMG points.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| TTN | NM_001267550.2 | c.96235G>A | p.Asp32079Asn | missense_variant | Exon 346 of 363 | ENST00000589042.5 | NP_001254479.2 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| TTN | ENST00000589042.5 | c.96235G>A | p.Asp32079Asn | missense_variant | Exon 346 of 363 | 5 | NM_001267550.2 | ENSP00000467141.1 |
Frequencies
GnomAD3 genomes 0.000204 AC: 31AN: 152070Hom.: 0 Cov.: 32 show subpopulations
GnomAD2 exomes AF: 0.000189 AC: 47AN: 248810 AF XY: 0.000156 show subpopulations
GnomAD4 exome AF: 0.000320 AC: 467AN: 1461440Hom.: 0 Cov.: 33 AF XY: 0.000303 AC XY: 220AN XY: 726994 show subpopulations
Age Distribution
GnomAD4 genome 0.000204 AC: 31AN: 152070Hom.: 0 Cov.: 32 AF XY: 0.000188 AC XY: 14AN XY: 74276 show subpopulations
Age Distribution
ClinVar
Submissions by phenotype
not provided Uncertain:3Benign:1
The TTN p.Asp23014Asn variant was not identified in the literature but was identified in dbSNP (ID: rs200540781), ClinVar (classified as uncertain significance by GeneDx, Invitae, Ambry Genetics, EGL Genetic Diagnostics, Laboratory for Molecular Medicine and Invitae) and LOVD 3.0 (classified as a VUS). The variant was identified in control databases in 51 of 280188 chromosomes at a frequency of 0.000182 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: Latino in 15 of 35360 chromosomes (freq: 0.000424), Other in 2 of 7126 chromosomes (freq: 0.000281), European (non-Finnish) in 32 of 128056 chromosomes (freq: 0.00025) and African in 2 of 24182 chromosomes (freq: 0.000083), but was not observed in the Ashkenazi Jewish, East Asian, European (Finnish), or South Asian populations. The p.Asp23014 residue has limited species conservation information and computational analyses (PolyPhen-2, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein. The variant occurs outside of the splicing consensus sequence and three of four in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing. However, this information is not predictive enough to assume pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -
- -
- -
- -
not specified Uncertain:1Benign:2
Variant summary: TTN c.88531G>A (p.Asp29511Asn) results in a conservative amino acid change located in the A-band domain of the encoded protein sequence. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00019 in 248810 control chromosomes, predominantly at a frequency of 0.00043 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 1.1 fold of the estimated maximal expected allele frequency for a pathogenic variant in TTN causing Dilated Cardiomyopathy phenotype (0.00039). c.88531G>A has been reported in the literature in individuals affected with sudden unexplained death/sudden infant death syndrome or fetal loss without evidence for causality (examples: Campuzano_2015, Kline_2021, Rohrer_2023). These report(s) do not provide unequivocal conclusions about association of the variant with Dilated Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 26516846, 34756330, 37614113). ClinVar contains an entry for this variant (Variation ID: 196196). Based on the evidence outlined above, the variant was classified as likely benign. -
The p.Asp29511Asn variant in TTN has not been previously reported in individuals with cardiomyopathy, but has been identified in 12/66690 European chromosomes a nd 6/11544 Latino chromosomes by the Exome Aggregation Consortium (ExAC, http:// exac.broadinstitute.org; dbSNP rs200540781). Computational prediction tools and conservation analysis suggest that this variant may impact the protein, though t his information is not predictive enough to determine pathogenicity. In summary, the clinical significance of the p.Asp29511Asn variant is uncertain. -
- -
Autosomal recessive limb-girdle muscular dystrophy type 2J Uncertain:1
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
TTN-related disorder Uncertain:1
The TTN c.96235G>A variant is predicted to result in the amino acid substitution p.Asp32079Asn. This variant was reported in individuals with sudden unexplained death; however, detailed clinical information was not available (described as p.29511D>N in Table S1, Campuzano et al. 2015. PubMed ID: 26516846; Rohrer et al. 2023. PubMed ID: 37614113). This variant is reported in 0.042% of alleles in individuals of Latino descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G Uncertain:1
- -
Dilated cardiomyopathy 1G Uncertain:1
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Early-onset myopathy with fatal cardiomyopathy Uncertain:1
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Primary dilated cardiomyopathy Uncertain:1
- -
Cardiomyopathy Benign:1
- -
Myopathy, myofibrillar, 9, with early respiratory failure Benign:1
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Tibial muscular dystrophy Benign:1
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Cardiovascular phenotype Benign:1
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at