rs72648954

Variant names:

• chr2-178728722-T-C
• rs72648954
• NM_001267550.2:c.19204A>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.19204A>G​(p.Met6402Val) variant causes a missense change. The variant allele was found at a frequency of 0.00312 in 1,611,378 control chromosomes in the GnomAD database, including 113 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M6402T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.015 (57 hom., cov: 33)
  • Exomes 𝑓: 0.0019 (56 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:26
• Conservation: PhyloP100: 4.99
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0014709234).
• BP6: Variant 2-178728722-T-C is Benign according to our data. Variant chr2-178728722-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 46655.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0153 (2329/152292) while in subpopulation AFR AF = 0.0516 (2147/41576). AF 95% confidence interval is 0.0498. There are 57 homozygotes in GnomAd4. There are 1073 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 57 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.19204A>G	p.Met6402Val	missense	Exon 66 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.18253A>G	p.Met6085Val	missense	Exon 64 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.15472A>G	p.Met5158Val	missense	Exon 63 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.19204A>G	p.Met6402Val	missense	Exon 66 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.19204A>G	p.Met6402Val	missense	Exon 66 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.18928A>G	p.Met6310Val	missense	Exon 64 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.0153 AC: 2327 AN: 152174 Hom.: 58 Cov.: 33

Gnomad AFR AF: 0.0517

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00662

Gnomad ASJ AF: 0.00634

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000338

Gnomad OTH AF: 0.0153

GnomAD2 exomes AF: 0.00410 AC: 1018 AN: 248182 AF XY: 0.00298

Gnomad AFR exome AF: 0.0515

Gnomad AMR exome AF: 0.00291

Gnomad ASJ exome AF: 0.00489

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000463

Gnomad OTH exome AF: 0.00283

GnomAD4 exome AF: 0.00185 AC: 2704 AN: 1459086 Hom.: 56 Cov.: 32 AF XY: 0.00162 AC XY: 1172 AN XY: 725286

African (AFR) AF: 0.0505 AC: 1689 AN: 33416

American (AMR) AF: 0.00358 AC: 160 AN: 44660

Ashkenazi Jewish (ASJ) AF: 0.00594 AC: 155 AN: 26098

East Asian (EAS) AF: 0.00 AC: 0 AN: 39584

South Asian (SAS) AF: 0.000128 AC: 11 AN: 86174

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53370

Middle Eastern (MID) AF: 0.00313 AC: 18 AN: 5748

European-Non Finnish (NFE) AF: 0.000354 AC: 393 AN: 1109778

Other (OTH) AF: 0.00461 AC: 278 AN: 60258

GnomAD4 genome AF: 0.0153 AC: 2329 AN: 152292 Hom.: 57 Cov.: 33 AF XY: 0.0144 AC XY: 1073 AN XY: 74454

African (AFR) AF: 0.0516 AC: 2147 AN: 41576

American (AMR) AF: 0.00661 AC: 101 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00634 AC: 22 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.000338 AC: 23 AN: 68014

Other (OTH) AF: 0.0151 AC: 32 AN: 2114

Alfa AF: 0.00560 Hom.: 60

Bravo AF: 0.0174

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0440 AC: 165

ESP6500EA AF: 0.000486 AC: 4

ExAC AF: 0.00484 AC: 585

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.000601

EpiControl AF: 0.000475

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)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.047
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	17
DANN	Benign	0.83
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.24
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.45	T
MetaRNN	Benign	0.0015	T
MetaSVM	Benign	-1.0	T
PhyloP100		5.0
PrimateAI	Benign	0.33	T
PROVEAN	Benign	0.92	N
REVEL	Benign	0.10
Sift	Benign	0.64	T
Polyphen		0.0	B
Vest4		0.094
MVP		0.088
MPC		0.085
ClinPred		0.0020	T
GERP RS		4.8
Mutation Taster		=81/19	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: rs72648954; hg19: chr2-179593449;