rs73038314

Variant names:

• chr2-178652503-C-T
• rs73038314
• NM_001267550.2:c.39082G>A

Your query was ambiguous. Multiple possible variants found:

• chr2-178652503-C-T
• chr2-178652503-C-A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001267550.2(TTN):​c.39082G>A​(p.Val13028Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00208 in 1,613,278 control chromosomes in the GnomAD database, including 51 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0093 (20 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (31 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:26
• Conservation: PhyloP100: 0.370
• Publications: 3 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]

LOC124906100 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002916038).
• BP6: Variant 2-178652503-C-T is Benign according to our data. Variant chr2-178652503-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 46917.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00931 (1415/151934) while in subpopulation AFR AF = 0.0312 (1294/41466). AF 95% confidence interval is 0.0298. There are 20 homozygotes in GnomAd4. There are 659 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 20 AD,AR gene

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.39082G>A	p.Val13028Met	missense	Exon 202 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.34561G>A	p.Val11521Met	missense	Exon 157 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.31780G>A	p.Val10594Met	missense	Exon 156 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.39082G>A	p.Val13028Met	missense	Exon 202 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.39082G>A	p.Val13028Met	missense	Exon 202 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.38806G>A	p.Val12936Met	missense	Exon 200 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.00933 AC: 1417 AN: 151810 Hom.: 20 Cov.: 32

Gnomad AFR AF: 0.0313

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00427

Gnomad ASJ AF: 0.00635

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.000309

Gnomad OTH AF: 0.00575

GnomAD2 exomes AF: 0.00277 AC: 689 AN: 248776 AF XY: 0.00221

Gnomad AFR exome AF: 0.0331

Gnomad AMR exome AF: 0.00200

Gnomad ASJ exome AF: 0.00547

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000408

Gnomad OTH exome AF: 0.00132

GnomAD4 exome AF: 0.00132 AC: 1934 AN: 1461344 Hom.: 31 Cov.: 33 AF XY: 0.00119 AC XY: 867 AN XY: 726952

African (AFR) AF: 0.0328 AC: 1097 AN: 33452

American (AMR) AF: 0.00235 AC: 105 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.00685 AC: 179 AN: 26118

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53398

Middle Eastern (MID) AF: 0.00261 AC: 15 AN: 5758

European-Non Finnish (NFE) AF: 0.000336 AC: 373 AN: 1111642

Other (OTH) AF: 0.00267 AC: 161 AN: 60342

GnomAD4 genome AF: 0.00931 AC: 1415 AN: 151934 Hom.: 20 Cov.: 32 AF XY: 0.00888 AC XY: 659 AN XY: 74242

African (AFR) AF: 0.0312 AC: 1294 AN: 41466

American (AMR) AF: 0.00426 AC: 65 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.00635 AC: 22 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5106

South Asian (SAS) AF: 0.00 AC: 0 AN: 4792

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

Middle Eastern (MID) AF: 0.00342 AC: 1 AN: 292

European-Non Finnish (NFE) AF: 0.000309 AC: 21 AN: 67930

Other (OTH) AF: 0.00569 AC: 12 AN: 2110

Alfa AF: 0.00177 Hom.: 5

Bravo AF: 0.0105

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0256 AC: 93

ESP6500EA AF: 0.000492 AC: 4

ExAC AF: 0.00324 AC: 391

Asia WGS AF: 0.00202 AC: 8 AN: 3478

EpiCase AF: 0.000655

EpiControl AF: 0.000533

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	10	not specified (10)
-	-	4	not provided (4)
-	-	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	Cardiomyopathy (1)
-	-	1	Dilated cardiomyopathy 1G (1)
-	-	1	TTN-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	13
DANN	Benign	0.89
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.25
FATHMM_MKL	Benign	0.021	N
LIST_S2	Benign	0.69	T
MetaRNN	Benign	0.0029	T
MetaSVM	Benign	-0.67	T
PhyloP100		0.37
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.16
Sift	Benign	0.052	T
Polyphen		0.12	B
Vest4		0.29
MVP		0.41
MPC		0.11
ClinPred		0.0089	T
GERP RS		3.4
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs73038314; hg19: chr2-179517230; COSMIC: COSV99045769; COSMIC: COSV99045769;