rs146983095

Variant names:

• chr2-178730645-T-C
• rs146983095
• NM_001267550.2:c.17888A>G

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.17888A>G​(p.Glu5963Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00971 in 1,613,676 control chromosomes in the GnomAD database, including 94 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0060 (0 hom., cov: 33)
  • Exomes 𝑓: 0.010 (94 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:27
• Conservation: PhyloP100: 5.05
• Publications: 10 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=0.0061029196).
• BP6: Variant 2-178730645-T-C is Benign according to our data. Variant chr2-178730645-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 46633.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00603 (918/152238) while in subpopulation NFE AF = 0.0106 (723/68010). AF 95% confidence interval is 0.00999. There are 0 homozygotes in GnomAd4. There are 401 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 94 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.17888A>G	p.Glu5963Gly	missense	Exon 61 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.16937A>G	p.Glu5646Gly	missense	Exon 59 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.14156A>G	p.Glu4719Gly	missense	Exon 58 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.17888A>G	p.Glu5963Gly	missense	Exon 61 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.17888A>G	p.Glu5963Gly	missense	Exon 61 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.17612A>G	p.Glu5871Gly	missense	Exon 59 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.00604 AC: 919 AN: 152120 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00232

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.00256

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00367

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0106

Gnomad OTH AF: 0.00478

GnomAD2 exomes AF: 0.00622 AC: 1543 AN: 248230 AF XY: 0.00640

Gnomad AFR exome AF: 0.00155

Gnomad AMR exome AF: 0.000957

Gnomad ASJ exome AF: 0.00130

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00478

Gnomad NFE exome AF: 0.0114

Gnomad OTH exome AF: 0.00398

GnomAD4 exome AF: 0.0101 AC: 14751 AN: 1461438 Hom.: 94 Cov.: 40 AF XY: 0.00984 AC XY: 7151 AN XY: 726992

African (AFR) AF: 0.00129 AC: 43 AN: 33458

American (AMR) AF: 0.00150 AC: 67 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.000995 AC: 26 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.00243 AC: 210 AN: 86256

European-Finnish (FIN) AF: 0.00582 AC: 311 AN: 53398

Middle Eastern (MID) AF: 0.000868 AC: 5 AN: 5762

European-Non Finnish (NFE) AF: 0.0123 AC: 13665 AN: 1111684

Other (OTH) AF: 0.00702 AC: 424 AN: 60356

GnomAD4 genome AF: 0.00603 AC: 918 AN: 152238 Hom.: 0 Cov.: 33 AF XY: 0.00539 AC XY: 401 AN XY: 74434

African (AFR) AF: 0.00231 AC: 96 AN: 41558

American (AMR) AF: 0.00255 AC: 39 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5166

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4826

European-Finnish (FIN) AF: 0.00367 AC: 39 AN: 10614

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

European-Non Finnish (NFE) AF: 0.0106 AC: 723 AN: 68010

Other (OTH) AF: 0.00473 AC: 10 AN: 2116

Alfa AF: 0.00923 Hom.: 33

Bravo AF: 0.00600

TwinsUK AF: 0.0146 AC: 54

ALSPAC AF: 0.0148 AC: 57

ESP6500AA AF: 0.00240 AC: 9

ESP6500EA AF: 0.0104 AC: 86

ExAC AF: 0.00698 AC: 843

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00928

EpiControl AF: 0.00883

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	9	not specified (9)
-	-	5	not provided (5)
-	-	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	Cardiovascular phenotype (1)
-	-	1	Dilated cardiomyopathy 1G (1)
-	-	1	Hypertrophic cardiomyopathy;C0878544:Cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	22
DANN	Benign	0.93
Eigen	Benign	-0.062
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.54	T
MetaRNN	Benign	0.0061	T
MetaSVM	Benign	-1.1	T
PhyloP100		5.0
PrimateAI	Benign	0.44	T
PROVEAN	Uncertain	-3.2	D
REVEL	Benign	0.11
Sift	Benign	0.33	T
Polyphen		0.0	B
Vest4		0.38
MVP		0.19
MPC		0.099
ClinPred		0.016	T
GERP RS		6.0
Mutation Taster		=82/18	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: rs146983095; hg19: chr2-179595372; COSMIC: COSV99045723; COSMIC: COSV99045723;