rs3829749

Variant names:

• chr2-178531033-G-A
• rs3829749
• NM_001267550.2:c.105582C>T

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.105582C>T​(p.Ser35194Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0324 in 1,613,774 control chromosomes in the GnomAD database, including 1,926 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.057 (445 hom., cov: 32)
  • Exomes 𝑓: 0.030 (1481 hom.)
• Consequence: TTN NM_001267550.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:22
• Conservation: PhyloP100: -3.76
• Publications: 6 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=-0.67).
• BP6: Variant 2-178531033-G-A is Benign according to our data. Variant chr2-178531033-G-A is described in ClinVar as Benign. ClinVar VariationId is 47694.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.76 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.156 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.105582C>T	p.Ser35194Ser	synonymous	Exon 358 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.100659C>T	p.Ser33553Ser	synonymous	Exon 308 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.97878C>T	p.Ser32626Ser	synonymous	Exon 307 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.105582C>T	p.Ser35194Ser	synonymous	Exon 358 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.105426C>T	p.Ser35142Ser	synonymous	Exon 356 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.105306C>T	p.Ser35102Ser	synonymous	Exon 356 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.0566 AC: 8597 AN: 151976 Hom.: 445 Cov.: 32

Gnomad AFR AF: 0.124

Gnomad AMI AF: 0.00879

Gnomad AMR AF: 0.0449

Gnomad ASJ AF: 0.0421

Gnomad EAS AF: 0.166

Gnomad SAS AF: 0.0472

Gnomad FIN AF: 0.00236

Gnomad MID AF: 0.0601

Gnomad NFE AF: 0.0202

Gnomad OTH AF: 0.0632

GnomAD2 exomes AF: 0.0436 AC: 10853 AN: 249140 AF XY: 0.0428

Gnomad AFR exome AF: 0.124

Gnomad AMR exome AF: 0.0337

Gnomad ASJ exome AF: 0.0417

Gnomad EAS exome AF: 0.176

Gnomad FIN exome AF: 0.00353

Gnomad NFE exome AF: 0.0207

Gnomad OTH exome AF: 0.0410

GnomAD4 exome AF: 0.0299 AC: 43736 AN: 1461678 Hom.: 1481 Cov.: 34 AF XY: 0.0301 AC XY: 21873 AN XY: 727124

African (AFR) AF: 0.125 AC: 4180 AN: 33478

American (AMR) AF: 0.0362 AC: 1618 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0425 AC: 1112 AN: 26136

East Asian (EAS) AF: 0.179 AC: 7102 AN: 39700

South Asian (SAS) AF: 0.0491 AC: 4232 AN: 86258

European-Finnish (FIN) AF: 0.00333 AC: 178 AN: 53376

Middle Eastern (MID) AF: 0.0973 AC: 561 AN: 5768

European-Non Finnish (NFE) AF: 0.0201 AC: 22394 AN: 1111866

Other (OTH) AF: 0.0391 AC: 2359 AN: 60374

GnomAD4 genome AF: 0.0566 AC: 8614 AN: 152096 Hom.: 445 Cov.: 32 AF XY: 0.0563 AC XY: 4183 AN XY: 74344

African (AFR) AF: 0.124 AC: 5135 AN: 41438

American (AMR) AF: 0.0449 AC: 686 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.0421 AC: 146 AN: 3470

East Asian (EAS) AF: 0.165 AC: 854 AN: 5178

South Asian (SAS) AF: 0.0476 AC: 229 AN: 4806

European-Finnish (FIN) AF: 0.00236 AC: 25 AN: 10598

Middle Eastern (MID) AF: 0.0646 AC: 19 AN: 294

European-Non Finnish (NFE) AF: 0.0203 AC: 1378 AN: 68006

Other (OTH) AF: 0.0634 AC: 134 AN: 2112

Alfa AF: 0.0339 Hom.: 412

Bravo AF: 0.0626

Asia WGS AF: 0.0980 AC: 338 AN: 3478

EpiCase AF: 0.0251

EpiControl AF: 0.0290

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	10	not specified (10)
-	-	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	Cardiovascular phenotype (1)
-	-	1	Dilated cardiomyopathy 1G (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	0.0010
DANN	Benign	0.74
PhyloP100		-3.8
Mutation Taster		=93/7	polymorphism (auto)

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: rs3829749; hg19: chr2-179395760; COSMIC: COSV60452970; COSMIC: COSV60452970;