rs35833641

Variant names:

• chr2-178597767-A-G
• rs35833641
• NM_001267550.2:c.57315T>C

Your query was ambiguous. Multiple possible variants found:

• chr2-178597767-A-G
• chr2-178597767-A-T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001267550.2(TTN):​c.57315T>C​(p.His19105His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.278 in 1,613,028 control chromosomes in the GnomAD database, including 67,882 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.21 (4605 hom., cov: 32)
  • Exomes 𝑓: 0.28 (63277 hom.)
• Consequence: TTN NM_001267550.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:24
• Conservation: PhyloP100: 1.43
• Publications: 21 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=-0.46).
• BP6: Variant 2-178597767-A-G is Benign according to our data. Variant chr2-178597767-A-G is described in ClinVar as Benign. ClinVar VariationId is 47120.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.43 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.306 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.57315T>C	p.His19105His	synonymous	Exon 294 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.52392T>C	p.His17464His	synonymous	Exon 244 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.49611T>C	p.His16537His	synonymous	Exon 243 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.57315T>C	p.His19105His	synonymous	Exon 294 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.57159T>C	p.His19053His	synonymous	Exon 292 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.57039T>C	p.His19013His	synonymous	Exon 292 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.213 AC: 32373 AN: 151966 Hom.: 4608 Cov.: 32

Gnomad AFR AF: 0.0534

Gnomad AMI AF: 0.219

Gnomad AMR AF: 0.152

Gnomad ASJ AF: 0.206

Gnomad EAS AF: 0.0468

Gnomad SAS AF: 0.217

Gnomad FIN AF: 0.386

Gnomad MID AF: 0.244

Gnomad NFE AF: 0.310

Gnomad OTH AF: 0.201

GnomAD2 exomes AF: 0.233 AC: 57747 AN: 247878 AF XY: 0.239

Gnomad AFR exome AF: 0.0470

Gnomad AMR exome AF: 0.111

Gnomad ASJ exome AF: 0.207

Gnomad EAS exome AF: 0.0386

Gnomad FIN exome AF: 0.383

Gnomad NFE exome AF: 0.305

Gnomad OTH exome AF: 0.234

GnomAD4 exome AF: 0.285 AC: 415872 AN: 1460944 Hom.: 63277 Cov.: 38 AF XY: 0.283 AC XY: 205816 AN XY: 726754

African (AFR) AF: 0.0415 AC: 1387 AN: 33446

American (AMR) AF: 0.113 AC: 5032 AN: 44666

Ashkenazi Jewish (ASJ) AF: 0.206 AC: 5379 AN: 26112

East Asian (EAS) AF: 0.0455 AC: 1798 AN: 39522

South Asian (SAS) AF: 0.217 AC: 18723 AN: 86232

European-Finnish (FIN) AF: 0.377 AC: 20151 AN: 53390

Middle Eastern (MID) AF: 0.205 AC: 1178 AN: 5756

European-Non Finnish (NFE) AF: 0.312 AC: 346776 AN: 1111494

Other (OTH) AF: 0.256 AC: 15448 AN: 60326

GnomAD4 genome AF: 0.213 AC: 32362 AN: 152084 Hom.: 4605 Cov.: 32 AF XY: 0.212 AC XY: 15753 AN XY: 74294

African (AFR) AF: 0.0532 AC: 2212 AN: 41556

American (AMR) AF: 0.152 AC: 2321 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.206 AC: 716 AN: 3470

East Asian (EAS) AF: 0.0467 AC: 240 AN: 5138

South Asian (SAS) AF: 0.217 AC: 1045 AN: 4820

European-Finnish (FIN) AF: 0.386 AC: 4070 AN: 10552

Middle Eastern (MID) AF: 0.248 AC: 73 AN: 294

European-Non Finnish (NFE) AF: 0.310 AC: 21064 AN: 67950

Other (OTH) AF: 0.199 AC: 421 AN: 2112

Alfa AF: 0.262 Hom.: 4736

Bravo AF: 0.184

Asia WGS AF: 0.124 AC: 431 AN: 3478

EpiCase AF: 0.295

EpiControl AF: 0.285

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	-0.46
CADD	Benign	0.41
DANN	Benign	0.67
PhyloP100		1.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=78/22	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: rs35833641; hg19: chr2-179462494; COSMIC: COSV60243979; COSMIC: COSV60243979;