rs146767076

Variant names:

• chr2-178573995-G-A
• rs146767076
• NM_001267550.2:c.72137C>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_001267550.2(TTN):​c.72137C>T​(p.Ala24046Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000237 in 1,613,350 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A24046A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0013 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00013 (0 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:14
• Conservation: PhyloP100: 3.19
• Publications: 3 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0046369135).
• BP6: Variant 2-178573995-G-A is Benign according to our data. Variant chr2-178573995-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 47309.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00129 (197/152196) while in subpopulation AFR AF = 0.00445 (185/41548). AF 95% confidence interval is 0.00393. There are 1 homozygotes in GnomAd4. There are 97 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	NM_001267550.2	MANE Select	c.72137C>T	p.Ala24046Val	missense	Exon 326 of 363	NP_001254479.2
	TTN	NM_001256850.1		c.67214C>T	p.Ala22405Val	missense	Exon 276 of 313	NP_001243779.1
	TTN	NM_133378.4		c.64433C>T	p.Ala21478Val	missense	Exon 275 of 312	NP_596869.4

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	ENST00000589042.5	TSL:5 MANE Select	c.72137C>T	p.Ala24046Val	missense	Exon 326 of 363	ENSP00000467141.1
	TTN	ENST00000446966.2	TSL:1	c.71981C>T	p.Ala23994Val	missense	Exon 324 of 361	ENSP00000408004.2
	TTN	ENST00000436599.2	TSL:1	c.71861C>T	p.Ala23954Val	missense	Exon 324 of 361	ENSP00000405517.2

Frequencies

GnomAD3 genomes AF: 0.00129 AC: 196 AN: 152078 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00444

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000656

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000363 AC: 90 AN: 248196 AF XY: 0.000356

Gnomad AFR exome AF: 0.00491

Gnomad AMR exome AF: 0.000319

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000890

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.000127 AC: 185 AN: 1461154 Hom.: 0 Cov.: 38 AF XY: 0.000106 AC XY: 77 AN XY: 726874

African (AFR) AF: 0.00457 AC: 153 AN: 33460

American (AMR) AF: 0.000336 AC: 15 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39538

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86240

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53374

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111612

Other (OTH) AF: 0.000215 AC: 13 AN: 60342

GnomAD4 genome AF: 0.00129 AC: 197 AN: 152196 Hom.: 1 Cov.: 33 AF XY: 0.00130 AC XY: 97 AN XY: 74396

African (AFR) AF: 0.00445 AC: 185 AN: 41548

American (AMR) AF: 0.000655 AC: 10 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5152

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67988

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000597 Hom.: 1

Bravo AF: 0.00130

ESP6500AA AF: 0.00371 AC: 14

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000389 AC: 47

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	5	not specified (5)
-	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	Benign	0.098
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	17
DANN	Benign	0.92
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.013
FATHMM_MKL	Benign	0.30	N
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.0046	T
MetaRNN	Benign	0.0046	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.035	N
PhyloP100		3.2
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.070
Sift	Benign	0.73	T
Polyphen		0.0	B
Vest4		0.15
MVP		0.24
MPC		0.083
ClinPred		0.015	T
GERP RS		4.8
Mutation Taster		=99/1	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: rs146767076; hg19: chr2-179438722; COSMIC: COSV104643010;