rs66677602

Variant names:

• chr2-178746984-C-A
• rs66677602
• NM_001267550.2:c.11312-5063G>T

Your query was ambiguous. Multiple possible variants found:

• chr2-178746984-C-A
• chr2-178746984-C-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_133379.5(TTN):​c.15416G>T​(p.Arg5139Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0531 in 1,613,354 control chromosomes in the GnomAD database, including 3,938 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.050 (385 hom., cov: 32)
  • Exomes 𝑓: 0.053 (3553 hom.)
• Consequence: TTN NM_133379.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.758
• Publications: 19 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=0.0011175871).
• BP6: Variant 2-178746984-C-A is Benign according to our data. Variant chr2-178746984-C-A is described in ClinVar as Benign. ClinVar VariationId is 47786.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.186 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_133379.5. 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.11312-5063G>T		intron	N/A	NP_001254479.2	Q8WZ42-12
	TTN	NM_133379.5		c.15416G>T	p.Arg5139Met	missense	Exon 46 of 46	NP_596870.2	Q8WZ42-6
	TTN	NM_001256850.1		c.10361-5063G>T		intron	N/A	NP_001243779.1	Q8WZ42-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	ENST00000589042.5	TSL:5 MANE Select	c.11312-5063G>T		intron	N/A	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.11312-5063G>T		intron	N/A	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.11036-5063G>T		intron	N/A	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.0503 AC: 7632 AN: 151880 Hom.: 384 Cov.: 32

Gnomad AFR AF: 0.0116

Gnomad AMI AF: 0.0482

Gnomad AMR AF: 0.137

Gnomad ASJ AF: 0.0488

Gnomad EAS AF: 0.196

Gnomad SAS AF: 0.0234

Gnomad FIN AF: 0.0512

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0454

Gnomad OTH AF: 0.0466

GnomAD2 exomes AF: 0.0803 AC: 20132 AN: 250760 AF XY: 0.0709

Gnomad AFR exome AF: 0.0109

Gnomad AMR exome AF: 0.241

Gnomad ASJ exome AF: 0.0485

Gnomad EAS exome AF: 0.217

Gnomad FIN exome AF: 0.0526

Gnomad NFE exome AF: 0.0445

Gnomad OTH exome AF: 0.0666

GnomAD4 exome AF: 0.0534 AC: 78002 AN: 1461356 Hom.: 3553 Cov.: 34 AF XY: 0.0516 AC XY: 37485 AN XY: 726982

African (AFR) AF: 0.00924 AC: 309 AN: 33446

American (AMR) AF: 0.229 AC: 10226 AN: 44660

Ashkenazi Jewish (ASJ) AF: 0.0473 AC: 1235 AN: 26108

East Asian (EAS) AF: 0.202 AC: 8029 AN: 39674

South Asian (SAS) AF: 0.0202 AC: 1742 AN: 86248

European-Finnish (FIN) AF: 0.0546 AC: 2917 AN: 53412

Middle Eastern (MID) AF: 0.0161 AC: 93 AN: 5760

European-Non Finnish (NFE) AF: 0.0453 AC: 50313 AN: 1111680

Other (OTH) AF: 0.0520 AC: 3138 AN: 60368

GnomAD4 genome AF: 0.0502 AC: 7635 AN: 151998 Hom.: 385 Cov.: 32 AF XY: 0.0517 AC XY: 3844 AN XY: 74294

African (AFR) AF: 0.0116 AC: 480 AN: 41502

American (AMR) AF: 0.138 AC: 2100 AN: 15240

Ashkenazi Jewish (ASJ) AF: 0.0488 AC: 169 AN: 3464

East Asian (EAS) AF: 0.196 AC: 1006 AN: 5132

South Asian (SAS) AF: 0.0228 AC: 110 AN: 4820

European-Finnish (FIN) AF: 0.0512 AC: 543 AN: 10606

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0454 AC: 3083 AN: 67926

Other (OTH) AF: 0.0452 AC: 95 AN: 2102

Alfa AF: 0.0518 Hom.: 1147

Bravo AF: 0.0612

TwinsUK AF: 0.0483 AC: 179

ALSPAC AF: 0.0493 AC: 190

ESP6500AA AF: 0.0136 AC: 60

ESP6500EA AF: 0.0433 AC: 372

ExAC AF: 0.0726 AC: 8816

Asia WGS AF: 0.0780 AC: 270 AN: 3478

EpiCase AF: 0.0408

EpiControl AF: 0.0431

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	17
DANN	Benign	0.95
Eigen	Benign	-0.0059
Eigen_PC	Benign	-0.024
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.35	T
MetaRNN	Benign	0.0011	T
MetaSVM	Benign	-1.0	T
PhyloP100		0.76
PROVEAN	Benign	1.1	N
REVEL	Benign	0.16
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.27	T
Polyphen		0.99	D
Vest4		0.20
ClinPred		0.022	T
GERP RS		5.2
Mutation Taster		=95/5	polymorphism (auto)

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: rs66677602; hg19: chr2-179611711; COSMIC: COSV59946596; COSMIC: COSV59946596;