NM_001267550.2:c.76922G>A

Variant names:

• chr2-178569210-C-T
• rs369707906
• NM_001267550.2:c.76922G>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.76922G>A​(p.Arg25641His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000497 in 1,606,956 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00029 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00052 (11 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:13
• Conservation: PhyloP100: 7.86
• Publications: 6 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=0.0067839324).
• BP6: Variant 2-178569210-C-T is Benign according to our data. Variant chr2-178569210-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 202874.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000289 (44/152184) while in subpopulation SAS AF = 0.00746 (36/4828). AF 95% confidence interval is 0.00554. There are 1 homozygotes in GnomAd4. There are 30 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 11 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.76922G>A	p.Arg25641His	missense	Exon 326 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.71999G>A	p.Arg24000His	missense	Exon 276 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.69218G>A	p.Arg23073His	missense	Exon 275 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.76922G>A	p.Arg25641His	missense	Exon 326 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.76766G>A	p.Arg25589His	missense	Exon 324 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.76646G>A	p.Arg25549His	missense	Exon 324 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.000289 AC: 44 AN: 152066 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00745

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000709 AC: 173 AN: 244032 AF XY: 0.000930

Gnomad AFR exome AF: 0.0000650

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: 0.0000270

Gnomad OTH exome AF: 0.000170

GnomAD4 exome AF: 0.000518 AC: 754 AN: 1454772 Hom.: 11 Cov.: 41 AF XY: 0.000661 AC XY: 478 AN XY: 722932

African (AFR) AF: 0.000151 AC: 5 AN: 33072

American (AMR) AF: 0.00 AC: 0 AN: 43952

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25766

East Asian (EAS) AF: 0.00 AC: 0 AN: 39624

South Asian (SAS) AF: 0.00576 AC: 489 AN: 84960

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53216

Middle Eastern (MID) AF: 0.000175 AC: 1 AN: 5724

European-Non Finnish (NFE) AF: 0.000211 AC: 234 AN: 1108408

Other (OTH) AF: 0.000416 AC: 25 AN: 60050

GnomAD4 genome AF: 0.000289 AC: 44 AN: 152184 Hom.: 1 Cov.: 33 AF XY: 0.000403 AC XY: 30 AN XY: 74410

African (AFR) AF: 0.0000962 AC: 4 AN: 41562

American (AMR) AF: 0.00 AC: 0 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5156

South Asian (SAS) AF: 0.00746 AC: 36 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

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

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 67972

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.0000846 Hom.: 0

Bravo AF: 0.000125

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.000836 AC: 101

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	3	not provided (3)
-	-	1	Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G (1)
-	-	1	Cardiomyopathy (1)
-	-	1	Cardiovascular phenotype (1)
-	1	-	Dilated Cardiomyopathy, Dominant (1)
-	1	-	Early-onset myopathy with fatal cardiomyopathy (1)
-	1	-	Hypertrophic cardiomyopathy (1)
-	1	-	Limb-girdle muscular dystrophy, recessive (1)
-	1	-	Myopathy, myofibrillar, 9, with early respiratory failure (1)
-	-	1	Sudden cardiac arrest (1)
-	1	-	Tibial muscular dystrophy (1)
-	-	1	TTN-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.72
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.17
CADD	Uncertain	23
DANN	Benign	0.91
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.95	D
MetaRNN	Benign	0.0068	T
MetaSVM	Uncertain	-0.029	T
MutationAssessor	Pathogenic	3.3	M
PhyloP100		7.9
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-3.6	D
REVEL	Uncertain	0.45
Sift	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.35
MVP		0.36
MPC		0.49
ClinPred		0.23	T
GERP RS		5.8
Mutation Taster		=93/7	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: rs369707906; hg19: chr2-179433937;