rs201944202

Variant names:

• chr2-178642297-C-A
• rs201944202
• NM_001267550.2:c.40498G>T

Your query was ambiguous. Multiple possible variants found:

• chr2-178642297-C-A
• chr2-178642297-C-T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001267550.2(TTN):​c.40498G>T​(p.Val13500Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00156 in 1,593,510 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00064 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0017 (3 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:18
• Conservation: PhyloP100: 1.53
• 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]

LOC124906100 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.02782479).
• BP6: Variant 2-178642297-C-A is Benign according to our data. Variant chr2-178642297-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 46935.
• BS1: Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.00165 (2383/1441598) while in subpopulation NFE AF = 0.0021 (2315/1101276). AF 95% confidence interval is 0.00203. There are 3 homozygotes in GnomAdExome4. There are 1151 alleles in the male GnomAdExome4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 3 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.40498G>T	p.Val13500Phe	missense	Exon 219 of 363	NP_001254479.2
	TTN	NM_001256850.1		c.35575G>T	p.Val11859Phe	missense	Exon 169 of 313	NP_001243779.1
	TTN	NM_133378.4		c.32794G>T	p.Val10932Phe	missense	Exon 168 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.40498G>T	p.Val13500Phe	missense	Exon 219 of 363	ENSP00000467141.1
	TTN	ENST00000436599.2	TSL:1	c.40222G>T	p.Val13408Phe	missense	Exon 217 of 361	ENSP00000405517.2
	TTN	ENST00000446966.2	TSL:1	c.40478-1667G>T		intron	N/A	ENSP00000408004.2

Frequencies

GnomAD3 genomes AF: 0.000639 AC: 97 AN: 151796 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000387

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000198

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00115

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000576 AC: 127 AN: 220530 AF XY: 0.000572

Gnomad AFR exome AF: 0.000148

Gnomad AMR exome AF: 0.0000638

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000493

Gnomad NFE exome AF: 0.00124

Gnomad OTH exome AF: 0.000182

GnomAD4 exome AF: 0.00165 AC: 2383 AN: 1441598 Hom.: 3 Cov.: 30 AF XY: 0.00161 AC XY: 1151 AN XY: 715386

African (AFR) AF: 0.000272 AC: 9 AN: 33076

American (AMR) AF: 0.0000474 AC: 2 AN: 42220

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25650

East Asian (EAS) AF: 0.00 AC: 0 AN: 39002

South Asian (SAS) AF: 0.0000121 AC: 1 AN: 82682

European-Finnish (FIN) AF: 0.000134 AC: 7 AN: 52432

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5730

European-Non Finnish (NFE) AF: 0.00210 AC: 2315 AN: 1101276

Other (OTH) AF: 0.000823 AC: 49 AN: 59530

GnomAD4 genome AF: 0.000639 AC: 97 AN: 151912 Hom.: 0 Cov.: 32 AF XY: 0.000552 AC XY: 41 AN XY: 74228

African (AFR) AF: 0.000385 AC: 16 AN: 41506

American (AMR) AF: 0.000197 AC: 3 AN: 15196

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10588

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

European-Non Finnish (NFE) AF: 0.00115 AC: 78 AN: 67864

Other (OTH) AF: 0.00 AC: 0 AN: 2104

Alfa AF: 0.00108 Hom.: 2

Bravo AF: 0.000657

TwinsUK AF: 0.00243 AC: 9

ALSPAC AF: 0.00337 AC: 13

ESP6500AA AF: 0.000277 AC: 1

ESP6500EA AF: 0.000492 AC: 4

ExAC AF: 0.000483 AC: 58

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	3	9	not provided (12)
-	-	3	not specified (3)
-	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	Cardiomyopathy (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)
-	-	1	TTN-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.090	T
Eigen	Benign	0.083
Eigen_PC	Benign	0.17
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Uncertain	0.86	D
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.028	T
MetaSVM	Benign	-0.76	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		1.5
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-2.8	D
REVEL	Benign	0.12
Sift	Uncertain	0.0040	D
Polyphen		0.41	B
Vest4		0.38
MVP		0.46
MPC		0.15
ClinPred		0.043	T
GERP RS		3.6
Mutation Taster		=86/14	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: rs201944202; hg19: chr2-179507024;