rs3813243

Variant names:

• chr2-178569789-C-T
• rs3813243
• NM_001267550.2:c.76343G>A

Your query was ambiguous. Multiple possible variants found:

• chr2-178569789-C-T
• chr2-178569789-C-A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001267550.2(TTN):​c.76343G>A​(p.Ser25448Asn) variant causes a missense change. The variant allele was found at a frequency of 0.0305 in 1,613,236 control chromosomes in the GnomAD database, including 1,521 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.043 (223 hom., cov: 32)
  • Exomes 𝑓: 0.029 (1298 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:23
• Conservation: PhyloP100: 5.30
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0015959144).
• BP6: Variant 2-178569789-C-T is Benign according to our data. Variant chr2-178569789-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 47347.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.157 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.76343G>A	p.Ser25448Asn	missense	Exon 326 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.71420G>A	p.Ser23807Asn	missense	Exon 276 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.68639G>A	p.Ser22880Asn	missense	Exon 275 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.76343G>A	p.Ser25448Asn	missense	Exon 326 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.76187G>A	p.Ser25396Asn	missense	Exon 324 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.76067G>A	p.Ser25356Asn	missense	Exon 324 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.0426 AC: 6474 AN: 152000 Hom.: 222 Cov.: 32

Gnomad AFR AF: 0.0706

Gnomad AMI AF: 0.00877

Gnomad AMR AF: 0.0391

Gnomad ASJ AF: 0.0424

Gnomad EAS AF: 0.167

Gnomad SAS AF: 0.0478

Gnomad FIN AF: 0.0192

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.0202

Gnomad OTH AF: 0.0555

GnomAD2 exomes AF: 0.0418 AC: 10385 AN: 248328 AF XY: 0.0419

Gnomad AFR exome AF: 0.0698

Gnomad AMR exome AF: 0.0314

Gnomad ASJ exome AF: 0.0422

Gnomad EAS exome AF: 0.181

Gnomad FIN exome AF: 0.0204

Gnomad NFE exome AF: 0.0209

Gnomad OTH exome AF: 0.0410

GnomAD4 exome AF: 0.0292 AC: 42684 AN: 1461116 Hom.: 1298 Cov.: 42 AF XY: 0.0296 AC XY: 21544 AN XY: 726860

African (AFR) AF: 0.0708 AC: 2368 AN: 33452

American (AMR) AF: 0.0332 AC: 1486 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.0429 AC: 1120 AN: 26116

East Asian (EAS) AF: 0.181 AC: 7183 AN: 39654

South Asian (SAS) AF: 0.0492 AC: 4241 AN: 86230

European-Finnish (FIN) AF: 0.0178 AC: 949 AN: 53224

Middle Eastern (MID) AF: 0.0962 AC: 554 AN: 5756

European-Non Finnish (NFE) AF: 0.0203 AC: 22528 AN: 1111630

Other (OTH) AF: 0.0374 AC: 2255 AN: 60346

GnomAD4 genome AF: 0.0426 AC: 6487 AN: 152120 Hom.: 223 Cov.: 32 AF XY: 0.0431 AC XY: 3207 AN XY: 74360

African (AFR) AF: 0.0707 AC: 2936 AN: 41538

American (AMR) AF: 0.0391 AC: 597 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.0424 AC: 147 AN: 3470

East Asian (EAS) AF: 0.167 AC: 857 AN: 5140

South Asian (SAS) AF: 0.0480 AC: 231 AN: 4808

European-Finnish (FIN) AF: 0.0192 AC: 204 AN: 10624

Middle Eastern (MID) AF: 0.0612 AC: 18 AN: 294

European-Non Finnish (NFE) AF: 0.0202 AC: 1371 AN: 67966

Other (OTH) AF: 0.0559 AC: 118 AN: 2112

Alfa AF: 0.0311 Hom.: 506

Bravo AF: 0.0456

TwinsUK AF: 0.0213 AC: 79

ALSPAC AF: 0.0189 AC: 73

ESP6500AA AF: 0.0640 AC: 241

ESP6500EA AF: 0.0202 AC: 167

ExAC AF: 0.0413 AC: 4987

Asia WGS AF: 0.102 AC: 353 AN: 3478

EpiCase AF: 0.0249

EpiControl AF: 0.0288

ClinVar

ClinVar submissions

Significance: Benign/Likely 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	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
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	20
DANN	Benign	0.82
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.80	T
MetaRNN	Benign	0.0016	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.81	L
PhyloP100		5.3
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.15
Sift	Benign	0.26	T
Polyphen		0.68	P
Vest4		0.30
MPC		0.15
ClinPred		0.032	T
GERP RS		5.9
Mutation Taster		=98/2	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: rs3813243; hg19: chr2-179434516; COSMIC: COSV60345066;