rs2306636

Variant names:

• chr2-178770209-C-T
• rs2306636
• NM_001267550.2:c.8492G>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.8492G>A​(p.Ser2831Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0547 in 1,614,076 control chromosomes in the GnomAD database, including 4,018 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.052 (389 hom., cov: 32)
  • Exomes 𝑓: 0.055 (3629 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:21
• Conservation: PhyloP100: 3.00
• Publications: 25 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=0.0010921359).
• BP6: Variant 2-178770209-C-T is Benign according to our data. Variant chr2-178770209-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 47527.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.175 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.8492G>A	p.Ser2831Asn	missense	Exon 36 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.8492G>A	p.Ser2831Asn	missense	Exon 36 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.8492G>A	p.Ser2831Asn	missense	Exon 36 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.8492G>A	p.Ser2831Asn	missense	Exon 36 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.8492G>A	p.Ser2831Asn	missense	Exon 36 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.8216G>A	p.Ser2739Asn	missense	Exon 34 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.0517 AC: 7860 AN: 152110 Hom.: 387 Cov.: 32

Gnomad AFR AF: 0.0119

Gnomad AMI AF: 0.0482

Gnomad AMR AF: 0.140

Gnomad ASJ AF: 0.0560

Gnomad EAS AF: 0.185

Gnomad SAS AF: 0.0464

Gnomad FIN AF: 0.0512

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0466

Gnomad OTH AF: 0.0483

GnomAD2 exomes AF: 0.0829 AC: 20816 AN: 251236 AF XY: 0.0746

Gnomad AFR exome AF: 0.0110

Gnomad AMR exome AF: 0.240

Gnomad ASJ exome AF: 0.0568

Gnomad EAS exome AF: 0.203

Gnomad FIN exome AF: 0.0525

Gnomad NFE exome AF: 0.0458

Gnomad OTH exome AF: 0.0699

GnomAD4 exome AF: 0.0550 AC: 80440 AN: 1461848 Hom.: 3629 Cov.: 33 AF XY: 0.0539 AC XY: 39165 AN XY: 727232

African (AFR) AF: 0.00989 AC: 331 AN: 33480

American (AMR) AF: 0.228 AC: 10215 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0552 AC: 1442 AN: 26136

East Asian (EAS) AF: 0.194 AC: 7681 AN: 39686

South Asian (SAS) AF: 0.0415 AC: 3578 AN: 86258

European-Finnish (FIN) AF: 0.0546 AC: 2918 AN: 53420

Middle Eastern (MID) AF: 0.0198 AC: 114 AN: 5768

European-Non Finnish (NFE) AF: 0.0457 AC: 50869 AN: 1111982

Other (OTH) AF: 0.0545 AC: 3292 AN: 60396

GnomAD4 genome AF: 0.0517 AC: 7866 AN: 152228 Hom.: 389 Cov.: 32 AF XY: 0.0537 AC XY: 3993 AN XY: 74412

African (AFR) AF: 0.0118 AC: 492 AN: 41562

American (AMR) AF: 0.140 AC: 2141 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0560 AC: 194 AN: 3466

East Asian (EAS) AF: 0.185 AC: 955 AN: 5158

South Asian (SAS) AF: 0.0465 AC: 224 AN: 4820

European-Finnish (FIN) AF: 0.0512 AC: 543 AN: 10598

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0466 AC: 3169 AN: 68008

Other (OTH) AF: 0.0468 AC: 99 AN: 2114

Alfa AF: 0.0527 Hom.: 1408

Bravo AF: 0.0618

TwinsUK AF: 0.0477 AC: 177

ALSPAC AF: 0.0506 AC: 195

ESP6500AA AF: 0.0134 AC: 59

ESP6500EA AF: 0.0451 AC: 388

ExAC AF: 0.0759 AC: 9220

Asia WGS AF: 0.0870 AC: 300 AN: 3476

EpiCase AF: 0.0427

EpiControl AF: 0.0453

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	9	not specified (9)
-	-	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	0.044
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	21
DANN	Benign	0.94
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.19
FATHMM_MKL	Benign	0.34	N
LIST_S2	Benign	0.33	T
MetaRNN	Benign	0.0011	T
MetaSVM	Benign	-1.1	T
PhyloP100		3.0
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	2.5	N
REVEL	Benign	0.14
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.016
MPC		0.078
ClinPred		0.011	T
GERP RS		6.1
Mutation Taster		=95/5	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: rs2306636; hg19: chr2-179634936; COSMIC: COSV59946607; COSMIC: COSV59946607;