chr2-178571098-G-A

Variant names:

• chr2-178571098-G-A
• rs368914555
• NM_001267550.2:c.75034C>T

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.75034C>T​(p.Arg25012Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00041 in 1,613,314 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R25012Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00026 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00043 (11 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:12
• Conservation: PhyloP100: 3.04
• 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: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007727444).
• BP6: Variant 2-178571098-G-A is Benign according to our data. Variant chr2-178571098-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 47335.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000256 (39/152090) while in subpopulation SAS AF = 0.00603 (29/4810). AF 95% confidence interval is 0.00431. There are 2 homozygotes in GnomAd4. There are 23 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 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.75034C>T	p.Arg25012Trp	missense	Exon 326 of 363	NP_001254479.2
	TTN	NM_001256850.1		c.70111C>T	p.Arg23371Trp	missense	Exon 276 of 313	NP_001243779.1
	TTN	NM_133378.4		c.67330C>T	p.Arg22444Trp	missense	Exon 275 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.75034C>T	p.Arg25012Trp	missense	Exon 326 of 363	ENSP00000467141.1
	TTN	ENST00000446966.2	TSL:1	c.74878C>T	p.Arg24960Trp	missense	Exon 324 of 361	ENSP00000408004.2
	TTN	ENST00000436599.2	TSL:1	c.74758C>T	p.Arg24920Trp	missense	Exon 324 of 361	ENSP00000405517.2

Frequencies

GnomAD3 genomes AF: 0.000250 AC: 38 AN: 151972 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.00582

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000736

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000882 AC: 219 AN: 248226 AF XY: 0.00111

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000580

Gnomad ASJ exome AF: 0.000698

Gnomad EAS exome AF: 0.000223

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000802

Gnomad OTH exome AF: 0.00116

GnomAD4 exome AF: 0.000426 AC: 622 AN: 1461224 Hom.: 11 Cov.: 40 AF XY: 0.000587 AC XY: 427 AN XY: 726892

African (AFR) AF: 0.000120 AC: 4 AN: 33452

American (AMR) AF: 0.0000895 AC: 4 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.000613 AC: 16 AN: 26120

East Asian (EAS) AF: 0.000176 AC: 7 AN: 39674

South Asian (SAS) AF: 0.00594 AC: 512 AN: 86240

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53296

Middle Eastern (MID) AF: 0.00278 AC: 16 AN: 5760

European-Non Finnish (NFE) AF: 0.0000297 AC: 33 AN: 1111616

Other (OTH) AF: 0.000497 AC: 30 AN: 60350

GnomAD4 genome AF: 0.000256 AC: 39 AN: 152090 Hom.: 2 Cov.: 32 AF XY: 0.000309 AC XY: 23 AN XY: 74332

African (AFR) AF: 0.00 AC: 0 AN: 41536

American (AMR) AF: 0.00 AC: 0 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.000865 AC: 3 AN: 3470

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5144

South Asian (SAS) AF: 0.00603 AC: 29 AN: 4810

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10596

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

European-Non Finnish (NFE) AF: 0.0000736 AC: 5 AN: 67950

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.000142 Hom.: 0

Bravo AF: 0.000128

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000120 AC: 1

ExAC AF: 0.000844 AC: 102

Asia WGS AF: 0.00173 AC: 6 AN: 3476

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	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	not provided (1)
-	-	1	Primary dilated cardiomyopathy (1)
-	-	1	Tibial muscular dystrophy (1)
-	-	1	TTN-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	18
DANN	Benign	0.90
Eigen	Uncertain	0.29
Eigen_PC	Benign	0.20
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.96	D
MetaRNN	Benign	0.0077	T
MetaSVM	Uncertain	-0.17	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		3.0
PrimateAI	Benign	0.43	T
PROVEAN	Pathogenic	-4.8	D
REVEL	Uncertain	0.34
Sift	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.37
MVP		0.32
MPC		0.44
ClinPred		0.14	T
GERP RS		3.5
Mutation Taster		=100/0	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: rs368914555; hg19: chr2-179435825; COSMIC: COSV59905944;