rs72648913

Variant names:

• chr2-178746240-C-T
• rs72648913
• NM_001267550.2:c.11312-4319G>A

Your query was ambiguous. Multiple possible variants found:

• chr2-178746240-C-T
• chr2-178746240-C-A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_133379.5(TTN):​c.16160G>A​(p.Cys5387Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00292 in 1,612,668 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0025 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0030 (8 hom.)
• Consequence: TTN NM_133379.5 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: 1.73
• Publications: 15 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=0.0126847625).
• BP6: Variant 2-178746240-C-T is Benign according to our data. Variant chr2-178746240-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 47795.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 = 0.00253 (385/152092) while in subpopulation NFE AF = 0.00374 (254/67932). AF 95% confidence interval is 0.00336. There are 1 homozygotes in GnomAd4. There are 191 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 8 AD,AR gene

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.11312-4319G>A		intron	N/A	NP_001254479.2	Q8WZ42-12
	TTN	NM_133379.5		c.16160G>A	p.Cys5387Tyr	missense	Exon 46 of 46	NP_596870.2	Q8WZ42-6
	TTN	NM_001256850.1		c.10361-4319G>A		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.11312-4319G>A		intron	N/A	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.11312-4319G>A		intron	N/A	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.11036-4319G>A		intron	N/A	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.00253 AC: 385 AN: 151974 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00302

Gnomad ASJ AF: 0.00289

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000830

Gnomad FIN AF: 0.00396

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00374

Gnomad OTH AF: 0.00383

GnomAD2 exomes AF: 0.00300 AC: 747 AN: 249308 AF XY: 0.00289

Gnomad AFR exome AF: 0.000247

Gnomad AMR exome AF: 0.00166

Gnomad ASJ exome AF: 0.00530

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00471

Gnomad NFE exome AF: 0.00439

Gnomad OTH exome AF: 0.00264

GnomAD4 exome AF: 0.00297 AC: 4331 AN: 1460576 Hom.: 8 Cov.: 33 AF XY: 0.00300 AC XY: 2177 AN XY: 726600

African (AFR) AF: 0.000509 AC: 17 AN: 33374

American (AMR) AF: 0.00166 AC: 74 AN: 44568

Ashkenazi Jewish (ASJ) AF: 0.00364 AC: 95 AN: 26074

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39616

South Asian (SAS) AF: 0.000847 AC: 73 AN: 86144

European-Finnish (FIN) AF: 0.00415 AC: 221 AN: 53214

Middle Eastern (MID) AF: 0.00486 AC: 28 AN: 5756

European-Non Finnish (NFE) AF: 0.00328 AC: 3649 AN: 1111516

Other (OTH) AF: 0.00287 AC: 173 AN: 60314

GnomAD4 genome AF: 0.00253 AC: 385 AN: 152092 Hom.: 1 Cov.: 32 AF XY: 0.00257 AC XY: 191 AN XY: 74360

African (AFR) AF: 0.000482 AC: 20 AN: 41534

American (AMR) AF: 0.00302 AC: 46 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.00289 AC: 10 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5162

South Asian (SAS) AF: 0.000830 AC: 4 AN: 4818

European-Finnish (FIN) AF: 0.00396 AC: 42 AN: 10612

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00374 AC: 254 AN: 67932

Other (OTH) AF: 0.00379 AC: 8 AN: 2112

Alfa AF: 0.00327 Hom.: 2

Bravo AF: 0.00232

TwinsUK AF: 0.00324 AC: 12

ALSPAC AF: 0.00259 AC: 10

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00407 AC: 35

ExAC AF: 0.00291 AC: 353

Asia WGS AF: 0.000578 AC: 2 AN: 3476

EpiCase AF: 0.00508

EpiControl AF: 0.00522

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	9	not provided (9)
-	-	4	not specified (4)
-	-	1	Hypertrophic cardiomyopathy (1)
-	-	1	TTN-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	23
DANN	Uncertain	0.98
Eigen	Benign	0.044
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.47	T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.013	T
MetaSVM	Benign	-0.88	T
PhyloP100		1.7
PROVEAN	Benign	-0.63	N
REVEL	Benign	0.083
Sift	Benign	0.039	D
Sift4G	Benign	0.087	T
Polyphen		0.22	B
Vest4		0.68
MVP		0.62
ClinPred		0.015	T
GERP RS		5.9
Mutation Taster		=91/9	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: rs72648913; hg19: chr2-179610967;