rs1479390801

Variant names:

• chr2-178662756-T-G
• rs1479390801
• NM_001267550.2:c.36847A>C

Variant summary

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

The NM_001267550.2(TTN):​c.36847A>C​(p.Lys12283Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 12/15 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000022 (0 hom., cov: 19)
  • Exomes 𝑓: 0.000043 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -1.57
• Publications: 0 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=0.034640253).

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.36847A>C	p.Lys12283Gln	missense	Exon 175 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.34354+210A>C		intron	N/A	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.31573+210A>C		intron	N/A	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.36847A>C	p.Lys12283Gln	missense	Exon 175 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.36847A>C	p.Lys12283Gln	missense	Exon 175 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.36571A>C	p.Lys12191Gln	missense	Exon 173 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.0000224 AC: 3 AN: 133686 Hom.: 0 Cov.: 19

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000797

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000177 AC: 10 AN: 56646 AF XY: 0.000247

Gnomad AFR exome AF: 0.000187

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000426 AC: 53 AN: 1244284 Hom.: 0 Cov.: 18 AF XY: 0.0000660 AC XY: 41 AN XY: 621328

African (AFR) AF: 0.0000353 AC: 1 AN: 28320

American (AMR) AF: 0.00 AC: 0 AN: 36176

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21936

East Asian (EAS) AF: 0.00 AC: 0 AN: 37602

South Asian (SAS) AF: 0.000611 AC: 46 AN: 75318

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37796

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3568

European-Non Finnish (NFE) AF: 0.00000315 AC: 3 AN: 951006

Other (OTH) AF: 0.0000571 AC: 3 AN: 52562

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000224 AC: 3 AN: 133780 Hom.: 0 Cov.: 19 AF XY: 0.0000312 AC XY: 2 AN XY: 64106

African (AFR) AF: 0.00 AC: 0 AN: 35296

American (AMR) AF: 0.00 AC: 0 AN: 12996

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3216

East Asian (EAS) AF: 0.00 AC: 0 AN: 4476

South Asian (SAS) AF: 0.000798 AC: 3 AN: 3760

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8672

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 274

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 62488

Other (OTH) AF: 0.00 AC: 0 AN: 1762

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	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 (1)
-	1	-	Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	0.35
DANN	Benign	0.80
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.033	N
LIST_S2	Benign	0.55	T
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.035	T
MetaSVM	Benign	-0.98	T
PhyloP100		-1.6
Vest4		0.090
MVP		0.24
MPC		0.12
ClinPred		0.018	T
GERP RS		-4.9
Mutation Taster		=100/0	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: rs1479390801; hg19: chr2-179527483; COSMIC: COSV59888242; COSMIC: COSV59888242;