rs4894045

Variant names:

• chr2-178768917-G-C
• rs4894045
• NM_001267550.2:c.8919C>G

Your query was ambiguous. Multiple possible variants found:

• chr2-178768917-G-C
• chr2-178768917-G-A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001267550.2(TTN):​c.8919C>G​(p.Ser2973Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.04 in 1,613,666 control chromosomes in the GnomAD database, including 3,048 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.054 (363 hom., cov: 31)
  • Exomes 𝑓: 0.039 (2685 hom.)
• Consequence: TTN NM_001267550.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:24
• Conservation: PhyloP100: 0.715
• Publications: 8 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 2-178768917-G-C is Benign according to our data. Variant chr2-178768917-G-C is described in ClinVar as Benign. ClinVar VariationId is 47571.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.715 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.153 is higher than 0.05.

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.8919C>G	p.Ser2973Ser	synonymous	Exon 38 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.8919C>G	p.Ser2973Ser	synonymous	Exon 38 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.8919C>G	p.Ser2973Ser	synonymous	Exon 38 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.8919C>G	p.Ser2973Ser	synonymous	Exon 38 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.8919C>G	p.Ser2973Ser	synonymous	Exon 38 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.8643C>G	p.Ser2881Ser	synonymous	Exon 36 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.0535 AC: 8141 AN: 152052 Hom.: 356 Cov.: 31

Gnomad AFR AF: 0.0698

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.135

Gnomad ASJ AF: 0.0259

Gnomad EAS AF: 0.0214

Gnomad SAS AF: 0.163

Gnomad FIN AF: 0.0576

Gnomad MID AF: 0.0287

Gnomad NFE AF: 0.0222

Gnomad OTH AF: 0.0378

GnomAD2 exomes AF: 0.0704 AC: 17653 AN: 250700 AF XY: 0.0692

Gnomad AFR exome AF: 0.0705

Gnomad AMR exome AF: 0.185

Gnomad ASJ exome AF: 0.0295

Gnomad EAS exome AF: 0.0252

Gnomad FIN exome AF: 0.0552

Gnomad NFE exome AF: 0.0232

Gnomad OTH exome AF: 0.0554

GnomAD4 exome AF: 0.0386 AC: 56387 AN: 1461494 Hom.: 2685 Cov.: 32 AF XY: 0.0413 AC XY: 30007 AN XY: 727046

African (AFR) AF: 0.0685 AC: 2294 AN: 33476

American (AMR) AF: 0.182 AC: 8151 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.0280 AC: 731 AN: 26128

East Asian (EAS) AF: 0.0124 AC: 493 AN: 39614

South Asian (SAS) AF: 0.162 AC: 13969 AN: 86232

European-Finnish (FIN) AF: 0.0563 AC: 3001 AN: 53268

Middle Eastern (MID) AF: 0.0470 AC: 271 AN: 5764

European-Non Finnish (NFE) AF: 0.0224 AC: 24887 AN: 1111930

Other (OTH) AF: 0.0429 AC: 2590 AN: 60378

GnomAD4 genome AF: 0.0536 AC: 8156 AN: 152172 Hom.: 363 Cov.: 31 AF XY: 0.0585 AC XY: 4350 AN XY: 74388

African (AFR) AF: 0.0698 AC: 2897 AN: 41502

American (AMR) AF: 0.136 AC: 2070 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.0259 AC: 90 AN: 3470

East Asian (EAS) AF: 0.0216 AC: 112 AN: 5186

South Asian (SAS) AF: 0.162 AC: 781 AN: 4822

European-Finnish (FIN) AF: 0.0576 AC: 610 AN: 10590

Middle Eastern (MID) AF: 0.0274 AC: 8 AN: 292

European-Non Finnish (NFE) AF: 0.0222 AC: 1509 AN: 68012

Other (OTH) AF: 0.0374 AC: 79 AN: 2112

Alfa AF: 0.0293 Hom.: 40

Bravo AF: 0.0565

Asia WGS AF: 0.106 AC: 366 AN: 3478

EpiCase AF: 0.0210

EpiControl AF: 0.0216

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	11	not specified (11)
-	-	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	not provided (2)
-	-	2	Tibial muscular dystrophy (2)
-	-	1	Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Dilated cardiomyopathy 1G (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	8.0
DANN	Benign	0.61
PhyloP100		0.71
Mutation Taster		=73/27	polymorphism (auto)

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: rs4894045; hg19: chr2-179633644; COSMIC: COSV60092789; COSMIC: COSV60092789;