rs398124448

Variant names:

• chr2-178659050-C-A
• rs398124448
• NM_001267550.2:c.37408G>T

Variant summary

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

The NM_001267550.2(TTN):​c.37408G>T​(p.Val12470Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 16/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00061 (0 hom., cov: 12)
  • Exomes 𝑓: 0.00067 (6 hom.)
  • Failed GnomAD Quality Control
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4 B:3 O:1
• Conservation: PhyloP100: -1.59
• Publications: 2 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]

LOC124906100 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.008723885).

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.37408G>T	p.Val12470Leu	missense	Exon 182 of 363	NP_001254479.2
	TTN	NM_001256850.1		c.34477G>T	p.Val11493Leu	missense	Exon 156 of 313	NP_001243779.1
	TTN	NM_133378.4		c.31696G>T	p.Val10566Leu	missense	Exon 155 of 312	NP_596869.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	ENST00000589042.5	TSL:5 MANE Select	c.37408G>T	p.Val12470Leu	missense	Exon 182 of 363	ENSP00000467141.1
	TTN	ENST00000446966.2	TSL:1	c.37408G>T	p.Val12470Leu	missense	Exon 182 of 361	ENSP00000408004.2
	TTN	ENST00000436599.2	TSL:1	c.37132G>T	p.Val12378Leu	missense	Exon 180 of 361	ENSP00000405517.2

Frequencies

GnomAD3 genomes AF: 0.000621 AC: 66 AN: 106206 Hom.: 0 Cov.: 12

Gnomad AFR AF: 0.000505

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00199

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00330

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000371

Gnomad OTH AF: 0.00223

GnomAD2 exomes AF: 0.000631 AC: 34 AN: 53888 AF XY: 0.000747

Gnomad AFR exome AF: 0.000371

Gnomad AMR exome AF: 0.00143

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000291

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000153

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000671 AC: 567 AN: 844384 Hom.: 6 Cov.: 11 AF XY: 0.000868 AC XY: 369 AN XY: 425084

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000331 AC: 7 AN: 21134

American (AMR) AF: 0.00156 AC: 33 AN: 21164

Ashkenazi Jewish (ASJ) AF: 0.000121 AC: 2 AN: 16540

East Asian (EAS) AF: 0.000267 AC: 9 AN: 33680

South Asian (SAS) AF: 0.00597 AC: 328 AN: 54930

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45042

Middle Eastern (MID) AF: 0.000713 AC: 2 AN: 2804

European-Non Finnish (NFE) AF: 0.000251 AC: 153 AN: 609660

Other (OTH) AF: 0.000837 AC: 33 AN: 39430

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.000611 AC: 65 AN: 106316 Hom.: 0 Cov.: 12 AF XY: 0.000635 AC XY: 32 AN XY: 50380

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000503 AC: 15 AN: 29834

American (AMR) AF: 0.00199 AC: 20 AN: 10058

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2716

East Asian (EAS) AF: 0.00 AC: 0 AN: 4256

South Asian (SAS) AF: 0.00298 AC: 9 AN: 3020

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5556

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 258

European-Non Finnish (NFE) AF: 0.000371 AC: 18 AN: 48558

Other (OTH) AF: 0.00219 AC: 3 AN: 1368

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000000000720757), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.000858 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	2	not provided (4)
-	2	-	Autosomal recessive limb-girdle muscular dystrophy type 2J;C1838244:Tibial muscular dystrophy;C1858763:Dilated cardiomyopathy 1G;C1861065:Hypertrophic cardiomyopathy 9;C1863599:Myopathy, myofibrillar, 9, with early respiratory failure;C2673677:Early-onset myopathy with fatal cardiomyopathy (2)
-	1	-	Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	5.4
DANN	Benign	0.67
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.73
FATHMM_MKL	Benign	0.072	N
LIST_S2	Benign	0.43	T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.0087	T
MetaSVM	Benign	-0.59	T
PhyloP100		-1.6
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.18
Sift	Benign	0.16	T
Polyphen		0.0010	B
Vest4		0.045
MutPred		0.36		Gain of glycosylation at P11498 (P = 0.1647)
MVP		0.31
MPC		0.15
ClinPred		0.021	T
GERP RS		1.7
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs398124448; hg19: chr2-179523777;