rs3829747

Variant names:

• chr2-178532834-C-T
• rs3829747
• NM_001267550.2:c.103781G>A

Your query was ambiguous. Multiple possible variants found:

• chr2-178532834-C-T
• chr2-178532834-C-G

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.103781G>A​(p.Arg34594His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.153 in 1,613,722 control chromosomes in the GnomAD database, including 21,854 homozygotes. In-silico tool predicts 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. R34594C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.14 (1970 hom., cov: 32)
  • Exomes 𝑓: 0.15 (19884 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:21
• Conservation: PhyloP100: 7.88
• Publications: 37 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=0.0026613176).
• BP6: Variant 2-178532834-C-T is Benign according to our data. Variant chr2-178532834-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 47663.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.424 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.103781G>A	p.Arg34594His	missense	Exon 358 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.98858G>A	p.Arg32953His	missense	Exon 308 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.96077G>A	p.Arg32026His	missense	Exon 307 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.103781G>A	p.Arg34594His	missense	Exon 358 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.103625G>A	p.Arg34542His	missense	Exon 356 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.103505G>A	p.Arg34502His	missense	Exon 356 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.141 AC: 21480 AN: 151996 Hom.: 1964 Cov.: 32

Gnomad AFR AF: 0.0748

Gnomad AMI AF: 0.474

Gnomad AMR AF: 0.128

Gnomad ASJ AF: 0.170

Gnomad EAS AF: 0.439

Gnomad SAS AF: 0.256

Gnomad FIN AF: 0.163

Gnomad MID AF: 0.114

Gnomad NFE AF: 0.145

Gnomad OTH AF: 0.126

GnomAD2 exomes AF: 0.176 AC: 43682 AN: 248810 AF XY: 0.180

Gnomad AFR exome AF: 0.0700

Gnomad AMR exome AF: 0.145

Gnomad ASJ exome AF: 0.170

Gnomad EAS exome AF: 0.430

Gnomad FIN exome AF: 0.152

Gnomad NFE exome AF: 0.144

Gnomad OTH exome AF: 0.158

GnomAD4 exome AF: 0.154 AC: 224708 AN: 1461608 Hom.: 19884 Cov.: 41 AF XY: 0.157 AC XY: 114029 AN XY: 727082

African (AFR) AF: 0.0708 AC: 2371 AN: 33476

American (AMR) AF: 0.145 AC: 6492 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.167 AC: 4375 AN: 26132

East Asian (EAS) AF: 0.433 AC: 17190 AN: 39694

South Asian (SAS) AF: 0.250 AC: 21594 AN: 86254

European-Finnish (FIN) AF: 0.152 AC: 8095 AN: 53384

Middle Eastern (MID) AF: 0.126 AC: 725 AN: 5768

European-Non Finnish (NFE) AF: 0.139 AC: 154084 AN: 1111810

Other (OTH) AF: 0.162 AC: 9782 AN: 60370

GnomAD4 genome AF: 0.141 AC: 21490 AN: 152114 Hom.: 1970 Cov.: 32 AF XY: 0.146 AC XY: 10847 AN XY: 74340

African (AFR) AF: 0.0746 AC: 3098 AN: 41504

American (AMR) AF: 0.127 AC: 1949 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.170 AC: 591 AN: 3472

East Asian (EAS) AF: 0.439 AC: 2268 AN: 5162

South Asian (SAS) AF: 0.255 AC: 1225 AN: 4804

European-Finnish (FIN) AF: 0.163 AC: 1723 AN: 10584

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

European-Non Finnish (NFE) AF: 0.145 AC: 9883 AN: 67982

Other (OTH) AF: 0.136 AC: 286 AN: 2110

Alfa AF: 0.148 Hom.: 8089

Bravo AF: 0.137

TwinsUK AF: 0.133 AC: 495

ALSPAC AF: 0.140 AC: 540

ESP6500AA AF: 0.0738 AC: 293

ESP6500EA AF: 0.144 AC: 1201

ExAC AF: 0.175 AC: 21163

Asia WGS AF: 0.340 AC: 1185 AN: 3478

EpiCase AF: 0.137

EpiControl AF: 0.141

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	-	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	Uncertain	0.53
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	22
DANN	Benign	0.95
Eigen	Uncertain	0.67
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.96	D
MetaRNN	Benign	0.0027	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.69	N
PhyloP100		7.9
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-3.6	D
REVEL	Uncertain	0.42
Sift	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.32
MPC		0.51
ClinPred		0.023	T
GERP RS		5.8
Mutation Taster		=92/8	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: rs3829747; hg19: chr2-179397561; COSMIC: COSV59894523; COSMIC: COSV59894523;