rs2742347

Variant names:

• chr2-178735921-C-T
• rs2742347
• NM_001267550.2:c.14525G>A

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.14525G>A​(p.Arg4842Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0669 in 1,613,726 control chromosomes in the GnomAD database, including 6,116 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 Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. R4842R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.11 (1400 hom., cov: 32)
  • Exomes 𝑓: 0.062 (4716 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:22
• Conservation: PhyloP100: 0.507
• Publications: 23 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=0.0045004487).
• BP6: Variant 2-178735921-C-T is Benign according to our data. Variant chr2-178735921-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 46586.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.213 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.14525G>A	p.Arg4842Lys	missense	Exon 50 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.13574G>A	p.Arg4525Lys	missense	Exon 48 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.10793G>A	p.Arg3598Lys	missense	Exon 47 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.14525G>A	p.Arg4842Lys	missense	Exon 50 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.14525G>A	p.Arg4842Lys	missense	Exon 50 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.14249G>A	p.Arg4750Lys	missense	Exon 48 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.111 AC: 16910 AN: 152018 Hom.: 1383 Cov.: 32

Gnomad AFR AF: 0.215

Gnomad AMI AF: 0.0482

Gnomad AMR AF: 0.162

Gnomad ASJ AF: 0.0712

Gnomad EAS AF: 0.189

Gnomad SAS AF: 0.0483

Gnomad FIN AF: 0.0511

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0481

Gnomad OTH AF: 0.100

GnomAD2 exomes AF: 0.0995 AC: 24778 AN: 248924 AF XY: 0.0877

Gnomad AFR exome AF: 0.215

Gnomad AMR exome AF: 0.252

Gnomad ASJ exome AF: 0.0717

Gnomad EAS exome AF: 0.209

Gnomad FIN exome AF: 0.0524

Gnomad NFE exome AF: 0.0475

Gnomad OTH exome AF: 0.0813

GnomAD4 exome AF: 0.0623 AC: 91014 AN: 1461590 Hom.: 4716 Cov.: 36 AF XY: 0.0603 AC XY: 43841 AN XY: 727086

African (AFR) AF: 0.220 AC: 7373 AN: 33476

American (AMR) AF: 0.241 AC: 10783 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.0720 AC: 1882 AN: 26128

East Asian (EAS) AF: 0.190 AC: 7525 AN: 39690

South Asian (SAS) AF: 0.0424 AC: 3659 AN: 86258

European-Finnish (FIN) AF: 0.0547 AC: 2920 AN: 53398

Middle Eastern (MID) AF: 0.0352 AC: 203 AN: 5766

European-Non Finnish (NFE) AF: 0.0471 AC: 52324 AN: 1111788

Other (OTH) AF: 0.0720 AC: 4345 AN: 60370

GnomAD4 genome AF: 0.112 AC: 16986 AN: 152136 Hom.: 1400 Cov.: 32 AF XY: 0.112 AC XY: 8332 AN XY: 74362

African (AFR) AF: 0.216 AC: 8975 AN: 41484

American (AMR) AF: 0.162 AC: 2477 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.0712 AC: 247 AN: 3470

East Asian (EAS) AF: 0.189 AC: 976 AN: 5160

South Asian (SAS) AF: 0.0485 AC: 234 AN: 4820

European-Finnish (FIN) AF: 0.0511 AC: 542 AN: 10604

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.0481 AC: 3273 AN: 68010

Other (OTH) AF: 0.0985 AC: 208 AN: 2112

Alfa AF: 0.0686 Hom.: 2065

Bravo AF: 0.130

TwinsUK AF: 0.0485 AC: 180

ALSPAC AF: 0.0503 AC: 194

ESP6500AA AF: 0.203 AC: 789

ESP6500EA AF: 0.0479 AC: 397

ExAC AF: 0.0958 AC: 11573

Asia WGS AF: 0.105 AC: 364 AN: 3476

EpiCase AF: 0.0449

EpiControl AF: 0.0475

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	9	not specified (9)
-	-	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	0.059
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	6.7
DANN	Benign	0.62
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.41
FATHMM_MKL	Benign	0.40	N
LIST_S2	Benign	0.26	T
MetaRNN	Benign	0.0045	T
MetaSVM	Benign	-1.1	T
PhyloP100		0.51
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.11	N
REVEL	Benign	0.049
Sift	Benign	0.97	T
Vest4		0.017
ClinPred		0.0030	T
GERP RS		1.8
Mutation Taster		=94/6	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: rs2742347; hg19: chr2-179600648; COSMIC: COSV59946464; COSMIC: COSV59946464;