rs744426

Variant names:

• chr2-178571293-G-A
• rs744426
• NM_001267550.2:c.74839C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-178571293-G-A
• chr2-178571293-G-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.74839C>T​(p.Arg24947Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.152 in 1,613,086 control chromosomes in the GnomAD database, including 21,744 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R24947G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.14 (1937 hom., cov: 32)
  • Exomes 𝑓: 0.15 (19807 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:23
• Conservation: PhyloP100: 3.32
• Publications: 34 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=0.003224939).
• BP6: Variant 2-178571293-G-A is Benign according to our data. Variant chr2-178571293-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 47329.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.425 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.74839C>T	p.Arg24947Cys	missense	Exon 326 of 363	NP_001254479.2
	TTN	NM_001256850.1		c.69916C>T	p.Arg23306Cys	missense	Exon 276 of 313	NP_001243779.1
	TTN	NM_133378.4		c.67135C>T	p.Arg22379Cys	missense	Exon 275 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.74839C>T	p.Arg24947Cys	missense	Exon 326 of 363	ENSP00000467141.1
	TTN	ENST00000446966.2	TSL:1	c.74683C>T	p.Arg24895Cys	missense	Exon 324 of 361	ENSP00000408004.2
	TTN	ENST00000436599.2	TSL:1	c.74563C>T	p.Arg24855Cys	missense	Exon 324 of 361	ENSP00000405517.2

Frequencies

GnomAD3 genomes AF: 0.141 AC: 21324 AN: 151706 Hom.: 1931 Cov.: 32

Gnomad AFR AF: 0.0753

Gnomad AMI AF: 0.467

Gnomad AMR AF: 0.127

Gnomad ASJ AF: 0.168

Gnomad EAS AF: 0.440

Gnomad SAS AF: 0.254

Gnomad FIN AF: 0.161

Gnomad MID AF: 0.114

Gnomad NFE AF: 0.144

Gnomad OTH AF: 0.125

GnomAD2 exomes AF: 0.175 AC: 43448 AN: 248268 AF XY: 0.179

Gnomad AFR exome AF: 0.0701

Gnomad AMR exome AF: 0.145

Gnomad ASJ exome AF: 0.169

Gnomad EAS exome AF: 0.428

Gnomad FIN exome AF: 0.152

Gnomad NFE exome AF: 0.143

Gnomad OTH exome AF: 0.157

GnomAD4 exome AF: 0.153 AC: 224047 AN: 1461262 Hom.: 19807 Cov.: 47 AF XY: 0.156 AC XY: 113673 AN XY: 726924

African (AFR) AF: 0.0711 AC: 2378 AN: 33442

American (AMR) AF: 0.145 AC: 6472 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.166 AC: 4336 AN: 26120

East Asian (EAS) AF: 0.433 AC: 17170 AN: 39650

South Asian (SAS) AF: 0.250 AC: 21530 AN: 86248

European-Finnish (FIN) AF: 0.151 AC: 8079 AN: 53396

Middle Eastern (MID) AF: 0.126 AC: 727 AN: 5760

European-Non Finnish (NFE) AF: 0.138 AC: 153606 AN: 1111590

Other (OTH) AF: 0.162 AC: 9749 AN: 60344

GnomAD4 genome AF: 0.141 AC: 21334 AN: 151824 Hom.: 1937 Cov.: 32 AF XY: 0.145 AC XY: 10763 AN XY: 74144

African (AFR) AF: 0.0751 AC: 3116 AN: 41468

American (AMR) AF: 0.126 AC: 1924 AN: 15230

Ashkenazi Jewish (ASJ) AF: 0.168 AC: 583 AN: 3468

East Asian (EAS) AF: 0.440 AC: 2250 AN: 5114

South Asian (SAS) AF: 0.253 AC: 1213 AN: 4794

European-Finnish (FIN) AF: 0.161 AC: 1697 AN: 10524

Middle Eastern (MID) AF: 0.122 AC: 36 AN: 294

European-Non Finnish (NFE) AF: 0.144 AC: 9808 AN: 67914

Other (OTH) AF: 0.134 AC: 284 AN: 2112

Alfa AF: 0.149 Hom.: 7331

Bravo AF: 0.136

TwinsUK AF: 0.133 AC: 493

ALSPAC AF: 0.140 AC: 539

ESP6500AA AF: 0.0746 AC: 288

ESP6500EA AF: 0.144 AC: 1195

ExAC AF: 0.174 AC: 21071

Asia WGS AF: 0.338 AC: 1178 AN: 3478

EpiCase AF: 0.136

EpiControl AF: 0.139

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely 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	0.14
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	22
DANN	Benign	0.85
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.97	D
MetaRNN	Benign	0.0032	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	2.0	M
PhyloP100		3.3
PrimateAI	Uncertain	0.60	T
PROVEAN	Pathogenic	-5.3	D
REVEL	Uncertain	0.30
Sift	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.29
MPC		0.47
ClinPred		0.048	T
GERP RS		4.5
Mutation Taster		=97/3	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: rs744426; hg19: chr2-179436020; COSMIC: COSV59894714;