rs17354992

Variant names:

• chr2-178621496-C-T
• rs17354992
• NM_001267550.2:c.45328G>A

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.45328G>A​(p.Asp15110Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00753 in 1,612,268 control chromosomes in the GnomAD database, including 83 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D15110G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0068 (12 hom., cov: 32)
  • Exomes 𝑓: 0.0076 (71 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:21
• Conservation: PhyloP100: 2.03
• Publications: 18 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004173279).
• BP6: Variant 2-178621496-C-T is Benign according to our data. Variant chr2-178621496-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 46987.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00678 (1031/151988) while in subpopulation NFE AF = 0.00782 (531/67906). AF 95% confidence interval is 0.00727. There are 12 homozygotes in GnomAd4. There are 582 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 12 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.45328G>A	p.Asp15110Asn	missense	Exon 245 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.40405G>A	p.Asp13469Asn	missense	Exon 195 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.37624G>A	p.Asp12542Asn	missense	Exon 194 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.45328G>A	p.Asp15110Asn	missense	Exon 245 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.45172G>A	p.Asp15058Asn	missense	Exon 243 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.45052G>A	p.Asp15018Asn	missense	Exon 243 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.00680 AC: 1032 AN: 151870 Hom.: 12 Cov.: 32

Gnomad AFR AF: 0.00126

Gnomad AMI AF: 0.00769

Gnomad AMR AF: 0.00395

Gnomad ASJ AF: 0.0110

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00642

Gnomad FIN AF: 0.0288

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00782

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00789 AC: 1955 AN: 247648 AF XY: 0.00794

Gnomad AFR exome AF: 0.00110

Gnomad AMR exome AF: 0.00236

Gnomad ASJ exome AF: 0.0122

Gnomad EAS exome AF: 0.0000563

Gnomad FIN exome AF: 0.0302

Gnomad NFE exome AF: 0.00724

Gnomad OTH exome AF: 0.00550

GnomAD4 exome AF: 0.00761 AC: 11106 AN: 1460280 Hom.: 71 Cov.: 32 AF XY: 0.00778 AC XY: 5653 AN XY: 726442

African (AFR) AF: 0.000958 AC: 32 AN: 33396

American (AMR) AF: 0.00229 AC: 102 AN: 44590

Ashkenazi Jewish (ASJ) AF: 0.0107 AC: 280 AN: 26078

East Asian (EAS) AF: 0.0000506 AC: 2 AN: 39516

South Asian (SAS) AF: 0.00845 AC: 728 AN: 86192

European-Finnish (FIN) AF: 0.0266 AC: 1418 AN: 53360

Middle Eastern (MID) AF: 0.000696 AC: 4 AN: 5750

European-Non Finnish (NFE) AF: 0.00736 AC: 8176 AN: 1111132

Other (OTH) AF: 0.00604 AC: 364 AN: 60266

GnomAD4 genome AF: 0.00678 AC: 1031 AN: 151988 Hom.: 12 Cov.: 32 AF XY: 0.00783 AC XY: 582 AN XY: 74294

African (AFR) AF: 0.00125 AC: 52 AN: 41516

American (AMR) AF: 0.00394 AC: 60 AN: 15224

Ashkenazi Jewish (ASJ) AF: 0.0110 AC: 38 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5114

South Asian (SAS) AF: 0.00622 AC: 30 AN: 4826

European-Finnish (FIN) AF: 0.0288 AC: 306 AN: 10618

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

European-Non Finnish (NFE) AF: 0.00782 AC: 531 AN: 67906

Other (OTH) AF: 0.00332 AC: 7 AN: 2110

Alfa AF: 0.00644 Hom.: 17

Bravo AF: 0.00437

TwinsUK AF: 0.00485 AC: 18

ALSPAC AF: 0.00545 AC: 21

ESP6500AA AF: 0.000502 AC: 2

ESP6500EA AF: 0.00962 AC: 80

ExAC AF: 0.00754 AC: 911

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.00595

EpiControl AF: 0.00492

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	10	not specified (10)
-	-	4	not provided (4)
-	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	Hypertrophic 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	Benign	0.086
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	22
DANN	Uncertain	0.98
Eigen	Benign	-0.11
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.86	D
MetaRNN	Benign	0.0042	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.20	N
PhyloP100		2.0
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.21
Sift	Benign	0.20	T
Polyphen		0.0020	B
Vest4		0.21
MVP		0.26
MPC		0.082
ClinPred		0.0060	T
GERP RS		5.3
Mutation Taster		=96/4	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: rs17354992; hg19: chr2-179486223; COSMIC: COSV60199444; COSMIC: COSV60199444;