rs73038337

Variant names:

• chr2-178720461-G-A
• rs73038337
• NM_001267550.2:c.23301C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_001267550.2(TTN):​c.23301C>T​(p.Ser7767Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000545 in 1,613,610 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0027 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00032 (2 hom.)
• Consequence: TTN NM_001267550.2 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:16
• Conservation: PhyloP100: -0.425
• 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 2-178720461-G-A is Benign according to our data. Variant chr2-178720461-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 46716.
• BP7: Synonymous conserved (PhyloP=-0.425 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00273 (415/152222) while in subpopulation AFR AF = 0.00946 (393/41542). AF 95% confidence interval is 0.00869. There are 1 homozygotes in GnomAd4. There are 196 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 2 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	NM_001267550.2	MANE Select	c.23301C>T	p.Ser7767Ser	synonymous	Exon 80 of 363	NP_001254479.2
	TTN	NM_001256850.1		c.22350C>T	p.Ser7450Ser	synonymous	Exon 78 of 313	NP_001243779.1
	TTN	NM_133378.4		c.19569C>T	p.Ser6523Ser	synonymous	Exon 77 of 312	NP_596869.4

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	ENST00000589042.5	TSL:5 MANE Select	c.23301C>T	p.Ser7767Ser	synonymous	Exon 80 of 363	ENSP00000467141.1
	TTN	ENST00000446966.2	TSL:1	c.23301C>T	p.Ser7767Ser	synonymous	Exon 80 of 361	ENSP00000408004.2
	TTN	ENST00000436599.2	TSL:1	c.23025C>T	p.Ser7675Ser	synonymous	Exon 78 of 361	ENSP00000405517.2

Frequencies

GnomAD3 genomes AF: 0.00273 AC: 415 AN: 152104 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00949

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.000955

GnomAD2 exomes AF: 0.000611 AC: 152 AN: 248642 AF XY: 0.000430

Gnomad AFR exome AF: 0.00917

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000557

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000889

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.000318 AC: 465 AN: 1461388 Hom.: 2 Cov.: 35 AF XY: 0.000257 AC XY: 187 AN XY: 726964

African (AFR) AF: 0.0120 AC: 401 AN: 33454

American (AMR) AF: 0.000335 AC: 15 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26118

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39690

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86242

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53394

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5762

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1111658

Other (OTH) AF: 0.000663 AC: 40 AN: 60356

GnomAD4 genome AF: 0.00273 AC: 415 AN: 152222 Hom.: 1 Cov.: 33 AF XY: 0.00263 AC XY: 196 AN XY: 74420

African (AFR) AF: 0.00946 AC: 393 AN: 41542

American (AMR) AF: 0.00111 AC: 17 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

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

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68000

Other (OTH) AF: 0.000945 AC: 2 AN: 2116

Alfa AF: 0.00101 Hom.: 0

Bravo AF: 0.00298

Asia WGS AF: 0.000866 AC: 4 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	3	not provided (3)
-	1	-	Autosomal recessive limb-girdle muscular dystrophy type 2J (1)
-	-	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)
-	1	-	Early-onset myopathy with fatal cardiomyopathy (1)
-	-	1	Myopathy, myofibrillar, 9, with early respiratory failure (1)
-	-	1	Tibial muscular dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.084
DANN	Benign	0.46
PhyloP100		-0.42
Mutation Taster		=92/8	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs73038337; hg19: chr2-179585188; COSMIC: COSV100601282; COSMIC: COSV100601282;