rs114331773

Variant names:

• chr2-178621618-T-A
• rs114331773
• NM_001267550.2:c.45206A>T

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.45206A>T​(p.Glu15069Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0038 in 1,612,528 control chromosomes in the GnomAD database, including 123 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.017 (58 hom., cov: 32)
  • Exomes 𝑓: 0.0024 (65 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:20
• Conservation: PhyloP100: 7.97
• Publications: 11 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=0.0041663945).
• BP6: Variant 2-178621618-T-A is Benign according to our data. Variant chr2-178621618-T-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 46983.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0532 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.45206A>T	p.Glu15069Val	missense	Exon 245 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.40283A>T	p.Glu13428Val	missense	Exon 195 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.37502A>T	p.Glu12501Val	missense	Exon 194 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.45206A>T	p.Glu15069Val	missense	Exon 245 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.45050A>T	p.Glu15017Val	missense	Exon 243 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.44930A>T	p.Glu14977Val	missense	Exon 243 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.0169 AC: 2565 AN: 151820 Hom.: 59 Cov.: 32

Gnomad AFR AF: 0.0552

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00940

Gnomad ASJ AF: 0.0150

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000692

Gnomad OTH AF: 0.0168

GnomAD2 exomes AF: 0.00522 AC: 1291 AN: 247502 AF XY: 0.00445

Gnomad AFR exome AF: 0.0564

Gnomad AMR exome AF: 0.00401

Gnomad ASJ exome AF: 0.0171

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000681

Gnomad OTH exome AF: 0.00465

GnomAD4 exome AF: 0.00244 AC: 3558 AN: 1460590 Hom.: 65 Cov.: 32 AF XY: 0.00226 AC XY: 1642 AN XY: 726594

African (AFR) AF: 0.0571 AC: 1907 AN: 33404

American (AMR) AF: 0.00455 AC: 203 AN: 44630

Ashkenazi Jewish (ASJ) AF: 0.0171 AC: 445 AN: 26096

East Asian (EAS) AF: 0.00 AC: 0 AN: 39564

South Asian (SAS) AF: 0.000278 AC: 24 AN: 86230

European-Finnish (FIN) AF: 0.0000375 AC: 2 AN: 53380

Middle Eastern (MID) AF: 0.00938 AC: 54 AN: 5758

European-Non Finnish (NFE) AF: 0.000506 AC: 562 AN: 1111226

Other (OTH) AF: 0.00599 AC: 361 AN: 60302

GnomAD4 genome AF: 0.0169 AC: 2564 AN: 151938 Hom.: 58 Cov.: 32 AF XY: 0.0165 AC XY: 1226 AN XY: 74246

African (AFR) AF: 0.0551 AC: 2284 AN: 41482

American (AMR) AF: 0.00939 AC: 143 AN: 15234

Ashkenazi Jewish (ASJ) AF: 0.0150 AC: 52 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5112

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.000692 AC: 47 AN: 67880

Other (OTH) AF: 0.0166 AC: 35 AN: 2108

Alfa AF: 0.00401 Hom.: 8

Bravo AF: 0.0199

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.0516 AC: 201

ESP6500EA AF: 0.00133 AC: 11

ExAC AF: 0.00577 AC: 697

Asia WGS AF: 0.00318 AC: 11 AN: 3476

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	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	Cardiomyopathy (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Dilated cardiomyopathy 1G (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	22
DANN	Benign	0.94
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.87	D
MetaRNN	Benign	0.0042	T
MetaSVM	Benign	-0.57	T
MutationAssessor	Benign	1.5	L
PhyloP100		8.0
PrimateAI	Uncertain	0.54	T
PROVEAN	Pathogenic	-5.0	D
REVEL	Uncertain	0.50
Sift	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.46
MVP		0.61
MPC		0.50
ClinPred		0.030	T
GERP RS		6.2
Mutation Taster		=96/4	polymorphism

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: rs114331773; hg19: chr2-179486345; COSMIC: COSV99045624; COSMIC: COSV99045624;