rs192528655
Variant summary
Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP2BP6BS1BS2
The NM_001267550.2(TTN):c.38902C>T(p.Pro12968Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000849 in 1,609,202 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. 9/14 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_001267550.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TTN | NM_001267550.2 | c.38902C>T | p.Pro12968Ser | missense_variant | 200/363 | ENST00000589042.5 | |
LOC124906100 | XR_007087318.1 | n.2185+8404G>A | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TTN | ENST00000589042.5 | c.38902C>T | p.Pro12968Ser | missense_variant | 200/363 | 5 | NM_001267550.2 | P1 | |
TTN-AS1 | ENST00000659121.1 | n.502+55224G>A | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes ? AF: 0.000909 AC: 138AN: 151806Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.00121 AC: 293AN: 241582Hom.: 2 AF XY: 0.00139 AC XY: 183AN XY: 131604
GnomAD4 exome AF: 0.000843 AC: 1229AN: 1457280Hom.: 10 Cov.: 34 AF XY: 0.000970 AC XY: 703AN XY: 724904
GnomAD4 genome ? AF: 0.000908 AC: 138AN: 151922Hom.: 0 Cov.: 31 AF XY: 0.00114 AC XY: 85AN XY: 74250
ClinVar
Submissions by phenotype
not provided Benign:2
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jul 01, 2024 | TTN: BS2 - |
Likely benign, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The TTN p.Pro12968Ser variant was not identified in the literature but was identified in dbSNP (ID: rs192528655) and ClinVar (classified as uncertain significance by Division of Genomic Diagnostics, Children's Hospital of Philadelphia, and likely benign by Invitae and CeGaT Praxis fuer Humangenetik Tuebingen). The variant was identified in control databases in 316 of 272918 chromosomes (2 homozygous) at a frequency of 0.001158 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: Ashkenazi Jewish in 70 of 9814 chromosomes (freq: 0.007133), South Asian in 107 of 29718 chromosomes (freq: 0.003601), Other in 13 of 6870 chromosomes (freq: 0.001892), European (Finnish) in 27 of 24698 chromosomes (freq: 0.001093), European (non-Finnish) in 79 of 125250 chromosomes (freq: 0.000631), Latino in 19 of 34082 chromosomes (freq: 0.000558) and African in 1 of 23322 chromosomes (freq: 0.000043), but was not observed in the East Asian population. The p.Pro12968 residue has limited species conservation data and computational analyses (BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia | Sep 18, 2015 | - - |
Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 30, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at