rs202014478

Variant names:

• chr2-178672473-C-T
• rs202014478
• NM_001267550.2:c.34864G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001267550.2(TTN):​c.34864G>A​(p.Val11622Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00425 in 1,599,106 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. V11622V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0028 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0044 (12 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:21
• Conservation: PhyloP100: 0.00300
• 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]

LOC124906100 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004096329).
• BP6: Variant 2-178672473-C-T is Benign according to our data. Variant chr2-178672473-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 46909.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00279 (424/151744) while in subpopulation NFE AF = 0.00499 (338/67748). AF 95% confidence interval is 0.00455. There are 0 homozygotes in GnomAd4. There are 182 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 12 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.34864G>A	p.Val11622Ile	missense	Exon 154 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.33742G>A	p.Val11248Ile	missense	Exon 150 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.30961G>A	p.Val10321Ile	missense	Exon 149 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.34864G>A	p.Val11622Ile	missense	Exon 154 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.34864G>A	p.Val11622Ile	missense	Exon 154 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.34588G>A	p.Val11530Ile	missense	Exon 152 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.00280 AC: 424 AN: 151626 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000605

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00224

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00170

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00499

Gnomad OTH AF: 0.00240

GnomAD2 exomes AF: 0.00330 AC: 780 AN: 236296 AF XY: 0.00328

Gnomad AFR exome AF: 0.000857

Gnomad AMR exome AF: 0.00118

Gnomad ASJ exome AF: 0.000981

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00210

Gnomad NFE exome AF: 0.00598

Gnomad OTH exome AF: 0.00320

GnomAD4 exome AF: 0.00440 AC: 6367 AN: 1447362 Hom.: 12 Cov.: 31 AF XY: 0.00427 AC XY: 3068 AN XY: 719340

African (AFR) AF: 0.000866 AC: 28 AN: 32324

American (AMR) AF: 0.00149 AC: 62 AN: 41750

Ashkenazi Jewish (ASJ) AF: 0.000828 AC: 21 AN: 25376

East Asian (EAS) AF: 0.00 AC: 0 AN: 39618

South Asian (SAS) AF: 0.000219 AC: 18 AN: 82296

European-Finnish (FIN) AF: 0.00187 AC: 99 AN: 52942

Middle Eastern (MID) AF: 0.00141 AC: 8 AN: 5662

European-Non Finnish (NFE) AF: 0.00535 AC: 5922 AN: 1107754

Other (OTH) AF: 0.00350 AC: 209 AN: 59640

GnomAD4 genome AF: 0.00279 AC: 424 AN: 151744 Hom.: 0 Cov.: 32 AF XY: 0.00245 AC XY: 182 AN XY: 74170

African (AFR) AF: 0.000603 AC: 25 AN: 41464

American (AMR) AF: 0.00224 AC: 34 AN: 15192

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

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

European-Finnish (FIN) AF: 0.00170 AC: 18 AN: 10566

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00499 AC: 338 AN: 67748

Other (OTH) AF: 0.00237 AC: 5 AN: 2106

Alfa AF: 0.00406 Hom.: 7

Bravo AF: 0.00297

TwinsUK AF: 0.00512 AC: 19

ALSPAC AF: 0.00337 AC: 13

ESP6500AA AF: 0.00137 AC: 5

ESP6500EA AF: 0.00356 AC: 29

ExAC AF: 0.00364 AC: 440

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	10	not specified (10)
-	-	5	not provided (5)
-	1	-	Autosomal recessive limb-girdle muscular dystrophy type 2J (1)
-	-	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)
-	1	-	Early-onset myopathy with fatal cardiomyopathy (1)
-	-	1	Myopathy, myofibrillar, 9, with early respiratory failure (1)
-	-	1	Tibial muscular dystrophy (1)
-	-	1	TTN-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	17
DANN	Benign	0.96
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.12
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.41	T
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.0041	T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	1.2	L
PhyloP100		0.0030
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.28	N
REVEL	Benign	0.096
Sift	Benign	0.27	T
Polyphen		0.0	B
Vest4		0.094
MVP		0.37
MPC		0.069
ClinPred		0.0060	T
GERP RS		5.2
PromoterAI		0.0056	Neutral
Mutation Taster		=89/11	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs202014478; hg19: chr2-179537200; COSMIC: COSV105913479; COSMIC: COSV105913479;