rs371943746

Variant names:

• chr2-178617228-C-T
• rs371943746
• NM_001267550.2:c.47767G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001267550.2(TTN):​c.47767G>A​(p.Gly15923Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000115 in 1,543,872 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00043 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000080 (0 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:10 B:3
• Conservation: PhyloP100: 7.85
• Publications: 1 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]

ENSG00000271141 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.04079798).

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.47767G>A	p.Gly15923Arg	missense	Exon 255 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.42844G>A	p.Gly14282Arg	missense	Exon 205 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.40063G>A	p.Gly13355Arg	missense	Exon 204 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.47767G>A	p.Gly15923Arg	missense	Exon 255 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.47611G>A	p.Gly15871Arg	missense	Exon 253 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.47491G>A	p.Gly15831Arg	missense	Exon 253 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.000428 AC: 65 AN: 151766 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000967

Gnomad AMI AF: 0.0110

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000195

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000946

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000133

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.000145 AC: 23 AN: 158418 AF XY: 0.000143

Gnomad AFR exome AF: 0.000850

Gnomad AMR exome AF: 0.000182

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000931

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000151

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000805 AC: 112 AN: 1391990 Hom.: 0 Cov.: 31 AF XY: 0.0000858 AC XY: 59 AN XY: 687326

African (AFR) AF: 0.000625 AC: 19 AN: 30406

American (AMR) AF: 0.000154 AC: 5 AN: 32414

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24826

East Asian (EAS) AF: 0.00 AC: 0 AN: 36432

South Asian (SAS) AF: 0.0000264 AC: 2 AN: 75752

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50194

Middle Eastern (MID) AF: 0.000178 AC: 1 AN: 5616

European-Non Finnish (NFE) AF: 0.0000686 AC: 74 AN: 1078682

Other (OTH) AF: 0.000191 AC: 11 AN: 57668

GnomAD4 genome AF: 0.000428 AC: 65 AN: 151882 Hom.: 0 Cov.: 32 AF XY: 0.000444 AC XY: 33 AN XY: 74242

African (AFR) AF: 0.000964 AC: 40 AN: 41480

American (AMR) AF: 0.000197 AC: 3 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.000195 AC: 1 AN: 5120

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.0000946 AC: 1 AN: 10574

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

European-Non Finnish (NFE) AF: 0.000133 AC: 9 AN: 67862

Other (OTH) AF: 0.000474 AC: 1 AN: 2110

Alfa AF: 0.000329 Hom.: 0

Bravo AF: 0.000574

ESP6500AA AF: 0.00111 AC: 4

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000154 AC: 18

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	3	1	not provided (4)
-	2	-	not specified (2)
-	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	-	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	Tibial muscular dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.50
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	22
DANN	Benign	0.72
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.053	D
MetaRNN	Benign	0.041	T
MetaSVM	Benign	-0.38	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		7.8
PrimateAI	Uncertain	0.65	T
PROVEAN	Pathogenic	-5.7	D
REVEL	Uncertain	0.38
Sift	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.52
MutPred		0.62		Gain of MoRF binding (P = 0.0068)
MVP		0.41
MPC		0.48
ClinPred		0.13	T
GERP RS		6.0
Mutation Taster		=62/38	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs371943746; hg19: chr2-179481955;