2-178635975-C-T

Variant names:

• chr2-178635975-C-T
• rs375474669
• NM_001267550.2:c.41596G>A

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_Moderate BP6

The NM_001267550.2(TTN):​c.41596G>A​(p.Val13866Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000783 in 1,595,996 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000092 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000077 (0 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:2
• Conservation: PhyloP100: 7.82
• Publications: 7 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: Likely_benign. The variant received -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.12273577).
• BP6: Variant 2-178635975-C-T is Benign according to our data. Variant chr2-178635975-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 167786.

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.41596G>A	p.Val13866Ile	missense	Exon 226 of 363	NP_001254479.2
	TTN	NM_001256850.1		c.36673G>A	p.Val12225Ile	missense	Exon 176 of 313	NP_001243779.1
	TTN	NM_133378.4		c.33892G>A	p.Val11298Ile	missense	Exon 175 of 312	NP_596869.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	ENST00000589042.5	TSL:5 MANE Select	c.41596G>A	p.Val13866Ile	missense	Exon 226 of 363	ENSP00000467141.1
	TTN	ENST00000446966.2	TSL:1	c.41440G>A	p.Val13814Ile	missense	Exon 224 of 361	ENSP00000408004.2
	TTN	ENST00000436599.2	TSL:1	c.41320G>A	p.Val13774Ile	missense	Exon 224 of 361	ENSP00000405517.2

Frequencies

GnomAD3 genomes AF: 0.0000921 AC: 14 AN: 152042 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000883

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.000101 AC: 24 AN: 238266 AF XY: 0.0000775

Gnomad AFR exome AF: 0.000130

Gnomad AMR exome AF: 0.000121

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000113

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000740

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000769 AC: 111 AN: 1443836 Hom.: 0 Cov.: 32 AF XY: 0.0000755 AC XY: 54 AN XY: 715592

African (AFR) AF: 0.0000303 AC: 1 AN: 33022

American (AMR) AF: 0.000116 AC: 5 AN: 43172

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25184

East Asian (EAS) AF: 0.0000508 AC: 2 AN: 39370

South Asian (SAS) AF: 0.000215 AC: 18 AN: 83758

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52942

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5678

European-Non Finnish (NFE) AF: 0.0000754 AC: 83 AN: 1101210

Other (OTH) AF: 0.0000336 AC: 2 AN: 59500

GnomAD4 genome AF: 0.0000920 AC: 14 AN: 152160 Hom.: 0 Cov.: 32 AF XY: 0.0000672 AC XY: 5 AN XY: 74370

African (AFR) AF: 0.0000481 AC: 2 AN: 41544

American (AMR) AF: 0.000196 AC: 3 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5148

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

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

European-Non Finnish (NFE) AF: 0.0000883 AC: 6 AN: 67970

Other (OTH) AF: 0.000474 AC: 1 AN: 2110

Alfa AF: 0.0000299 Hom.: 0

Bravo AF: 0.0000604

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000121 AC: 1

ExAC AF: 0.0000828 AC: 10

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	3	1	not provided (4)
-	1	-	Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G (1)
-	1	-	Cardiomyopathy (1)
-	-	1	Cardiovascular phenotype (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	23
DANN	Benign	0.90
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-1.2	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		7.8
PrimateAI	Uncertain	0.48	T
PROVEAN	Benign	-0.80	N
REVEL	Benign	0.25
Sift	Benign	0.13	T
Polyphen		1.0	D
Vest4		0.30
MVP		0.45
MPC		0.42
ClinPred		0.088	T
GERP RS		5.7
Mutation Taster		=95/5	polymorphism

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: rs375474669; hg19: chr2-179500702; COSMIC: COSV59920926; COSMIC: COSV59920926;