chr2-178717108-C-A

Variant names:

• chr2-178717108-C-A
• rs2562832
• NM_001267550.2:c.25626G>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001267550.2(TTN):​c.25626G>T​(p.Gln8542His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0273 in 1,611,654 control chromosomes in the GnomAD database, including 1,379 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. Q8542Q) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.026 (147 hom., cov: 33)
  • Exomes 𝑓: 0.027 (1232 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:23
• Conservation: PhyloP100: -1.35
• Publications: 15 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0014437139).
• BP6: Variant 2-178717108-C-A is Benign according to our data. Variant chr2-178717108-C-A is described in ClinVar as Benign. ClinVar VariationId is 46763.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.181 is higher than 0.05.

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.25626G>T	p.Gln8542His	missense	Exon 88 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.24675G>T	p.Gln8225His	missense	Exon 86 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.21894G>T	p.Gln7298His	missense	Exon 85 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.25626G>T	p.Gln8542His	missense	Exon 88 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.25626G>T	p.Gln8542His	missense	Exon 88 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.25350G>T	p.Gln8450His	missense	Exon 86 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.0260 AC: 3952 AN: 152104 Hom.: 148 Cov.: 33

Gnomad AFR AF: 0.00507

Gnomad AMI AF: 0.0307

Gnomad AMR AF: 0.0268

Gnomad ASJ AF: 0.0294

Gnomad EAS AF: 0.191

Gnomad SAS AF: 0.0120

Gnomad FIN AF: 0.0473

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0236

Gnomad OTH AF: 0.0254

GnomAD2 exomes AF: 0.0391 AC: 9686 AN: 247602 AF XY: 0.0361

Gnomad AFR exome AF: 0.00524

Gnomad AMR exome AF: 0.0414

Gnomad ASJ exome AF: 0.0259

Gnomad EAS exome AF: 0.210

Gnomad FIN exome AF: 0.0495

Gnomad NFE exome AF: 0.0236

Gnomad OTH exome AF: 0.0319

GnomAD4 exome AF: 0.0275 AC: 40073 AN: 1459432 Hom.: 1232 Cov.: 31 AF XY: 0.0268 AC XY: 19468 AN XY: 725730

African (AFR) AF: 0.00425 AC: 142 AN: 33388

American (AMR) AF: 0.0391 AC: 1749 AN: 44676

Ashkenazi Jewish (ASJ) AF: 0.0248 AC: 647 AN: 26048

East Asian (EAS) AF: 0.191 AC: 7564 AN: 39634

South Asian (SAS) AF: 0.00936 AC: 806 AN: 86070

European-Finnish (FIN) AF: 0.0514 AC: 2739 AN: 53314

Middle Eastern (MID) AF: 0.0101 AC: 58 AN: 5748

European-Non Finnish (NFE) AF: 0.0222 AC: 24689 AN: 1110272

Other (OTH) AF: 0.0279 AC: 1679 AN: 60282

GnomAD4 genome AF: 0.0259 AC: 3946 AN: 152222 Hom.: 147 Cov.: 33 AF XY: 0.0273 AC XY: 2028 AN XY: 74416

African (AFR) AF: 0.00505 AC: 210 AN: 41572

American (AMR) AF: 0.0268 AC: 409 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.0294 AC: 102 AN: 3470

East Asian (EAS) AF: 0.191 AC: 985 AN: 5156

South Asian (SAS) AF: 0.0114 AC: 55 AN: 4824

European-Finnish (FIN) AF: 0.0473 AC: 501 AN: 10594

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0236 AC: 1603 AN: 68006

Other (OTH) AF: 0.0241 AC: 51 AN: 2112

Alfa AF: 0.0269 Hom.: 519

Bravo AF: 0.0259

TwinsUK AF: 0.0256 AC: 95

ALSPAC AF: 0.0234 AC: 90

ESP6500AA AF: 0.00497 AC: 19

ESP6500EA AF: 0.0214 AC: 177

ExAC AF: 0.0389 AC: 4695

Asia WGS AF: 0.0690 AC: 238 AN: 3478

EpiCase AF: 0.0200

EpiControl AF: 0.0218

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	10	not specified (10)
-	-	2	Autosomal recessive limb-girdle muscular dystrophy type 2J (2)
-	-	2	Early-onset myopathy with fatal cardiomyopathy (2)
-	-	2	Myopathy, myofibrillar, 9, with early respiratory failure (2)
-	-	2	not provided (2)
-	-	2	Tibial muscular dystrophy (2)
-	-	1	Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Dilated cardiomyopathy 1G (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	9.7
DANN	Benign	0.73
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.79
FATHMM_MKL	Benign	0.060	N
LIST_S2	Benign	0.60	T
MetaRNN	Benign	0.0014	T
MetaSVM	Benign	-1.0	T
PhyloP100		-1.3
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.15
Sift	Benign	0.59	T
Vest4		0.065
MutPred		0.46		Loss of stability (P = 0.1135)
ClinPred		0.0086	T
GERP RS		-7.8
Mutation Taster		=96/4	polymorphism (auto)

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: rs2562832; hg19: chr2-179581835; COSMIC: COSV59946431; COSMIC: COSV59946431;