NM_001267550.2:c.89994G>A

Variant names:

• chr2-178552906-C-T
• rs142891278
• NM_001267550.2:c.89994G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_001267550.2(TTN):​c.89994G>A​(p.Ser29998Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00221 in 1,613,720 control chromosomes in the GnomAD database, including 53 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. S29998S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0018 (5 hom., cov: 33)
  • Exomes 𝑓: 0.0023 (48 hom.)
• Consequence: TTN NM_001267550.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:25
• Conservation: PhyloP100: 0.282
• Publications: 0 publications found

Genes affected

TTN (HGNC:12403): (titin) This gene encodes a large abundant protein of striated muscle. The product of this gene is divided into two regions, a N-terminal I-band and a C-terminal A-band. The I-band, which is the elastic part of the molecule, contains two regions of tandem immunoglobulin domains on either side of a PEVK region that is rich in proline, glutamate, valine and lysine. The A-band, which is thought to act as a protein-ruler, contains a mixture of immunoglobulin and fibronectin repeats, and possesses kinase activity. An N-terminal Z-disc region and a C-terminal M-line region bind to the Z-line and M-line of the sarcomere, respectively, so that a single titin molecule spans half the length of a sarcomere. Titin also contains binding sites for muscle associated proteins so it serves as an adhesion template for the assembly of contractile machinery in muscle cells. It has also been identified as a structural protein for chromosomes. Alternative splicing of this gene results in multiple transcript variants. Considerable variability exists in the I-band, the M-line and the Z-disc regions of titin. Variability in the I-band region contributes to the differences in elasticity of different titin isoforms and, therefore, to the differences in elasticity of different muscle types. Mutations in this gene are associated with familial hypertrophic cardiomyopathy 9, and autoantibodies to titin are produced in patients with the autoimmune disease scleroderma. [provided by RefSeq, Feb 2012]

TTN-AS1 (HGNC:44124): (TTN antisense RNA 1) This gene encodes a non-coding RNA transcribed from the opposite strand to the titin gene. [provided by RefSeq, Aug 2016]

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.36).
• BP6: Variant 2-178552906-C-T is Benign according to our data. Variant chr2-178552906-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 47494.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.282 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00182 (277/152200) while in subpopulation SAS AF = 0.0241 (116/4822). AF 95% confidence interval is 0.0205. There are 5 homozygotes in GnomAd4. There are 154 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001267550.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	NM_001267550.2	MANE Select	c.89994G>A	p.Ser29998Ser	synonymous	Exon 335 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.85071G>A	p.Ser28357Ser	synonymous	Exon 285 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.82290G>A	p.Ser27430Ser	synonymous	Exon 284 of 312	NP_596869.4	Q8WZ42-11

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	ENST00000589042.5	TSL:5 MANE Select	c.89994G>A	p.Ser29998Ser	synonymous	Exon 335 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.89838G>A	p.Ser29946Ser	synonymous	Exon 333 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.89718G>A	p.Ser29906Ser	synonymous	Exon 333 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.00180 AC: 274 AN: 152082 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00190

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0234

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00169

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00372 AC: 924 AN: 248300 AF XY: 0.00472

Gnomad AFR exome AF: 0.000194

Gnomad AMR exome AF: 0.000841

Gnomad ASJ exome AF: 0.000897

Gnomad EAS exome AF: 0.0000559

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00176

Gnomad OTH exome AF: 0.00349

GnomAD4 exome AF: 0.00225 AC: 3295 AN: 1461520 Hom.: 48 Cov.: 33 AF XY: 0.00286 AC XY: 2081 AN XY: 727030

African (AFR) AF: 0.000418 AC: 14 AN: 33476

American (AMR) AF: 0.000738 AC: 33 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.000842 AC: 22 AN: 26134

East Asian (EAS) AF: 0.000227 AC: 9 AN: 39656

South Asian (SAS) AF: 0.0210 AC: 1814 AN: 86250

European-Finnish (FIN) AF: 0.0000750 AC: 4 AN: 53362

Middle Eastern (MID) AF: 0.00433 AC: 25 AN: 5768

European-Non Finnish (NFE) AF: 0.00107 AC: 1193 AN: 1111792

Other (OTH) AF: 0.00300 AC: 181 AN: 60370

GnomAD4 genome AF: 0.00182 AC: 277 AN: 152200 Hom.: 5 Cov.: 33 AF XY: 0.00207 AC XY: 154 AN XY: 74398

African (AFR) AF: 0.000241 AC: 10 AN: 41540

American (AMR) AF: 0.00190 AC: 29 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.000864 AC: 3 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.0241 AC: 116 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10596

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00169 AC: 115 AN: 68006

Other (OTH) AF: 0.00189 AC: 4 AN: 2116

Alfa AF: 0.00122 Hom.: 0

Bravo AF: 0.00108

Asia WGS AF: 0.0130 AC: 45 AN: 3478

EpiCase AF: 0.00294

EpiControl AF: 0.00243

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	6	not provided (6)
-	-	2	Autosomal recessive limb-girdle muscular dystrophy type 2J (2)
-	-	2	Early-onset myopathy with fatal cardiomyopathy (2)
-	-	2	Myopathy, myofibrillar, 9, with early respiratory failure (2)
-	-	2	Tibial muscular dystrophy (2)
-	-	1	Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G (1)
-	-	1	Cardiomyopathy (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Dilated cardiomyopathy 1G (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.36
CADD	Benign	0.35
DANN	Benign	0.79
PhyloP100		0.28
Mutation Taster		=83/17	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs142891278; hg19: chr2-179417633; COSMIC: COSV60095399; COSMIC: COSV60095399;