rs4894028

Variant names:

• chr2-178539023-C-T
• rs4894028
• NM_001267550.2:c.98912G>A

Your query was ambiguous. Multiple possible variants found:

• chr2-178539023-C-T
• chr2-178539023-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.98912G>A​(p.Arg32971His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0452 in 1,613,644 control chromosomes in the GnomAD database, including 3,448 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.045 (359 hom., cov: 33)
  • Exomes 𝑓: 0.045 (3089 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:22
• Conservation: PhyloP100: 7.91
• Publications: 22 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=0.001673609).
• BP6: Variant 2-178539023-C-T is Benign according to our data. Variant chr2-178539023-C-T is described in ClinVar as Benign. ClinVar VariationId is 47610.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.166 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.98912G>A	p.Arg32971His	missense	Exon 353 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.93989G>A	p.Arg31330His	missense	Exon 303 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.91208G>A	p.Arg30403His	missense	Exon 302 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.98912G>A	p.Arg32971His	missense	Exon 353 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.98756G>A	p.Arg32919His	missense	Exon 351 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.98636G>A	p.Arg32879His	missense	Exon 351 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.0445 AC: 6772 AN: 152072 Hom.: 353 Cov.: 33

Gnomad AFR AF: 0.0134

Gnomad AMI AF: 0.0493

Gnomad AMR AF: 0.151

Gnomad ASJ AF: 0.0297

Gnomad EAS AF: 0.0237

Gnomad SAS AF: 0.176

Gnomad FIN AF: 0.0584

Gnomad MID AF: 0.0665

Gnomad NFE AF: 0.0304

Gnomad OTH AF: 0.0402

GnomAD2 exomes AF: 0.0742 AC: 18442 AN: 248558 AF XY: 0.0744

Gnomad AFR exome AF: 0.0119

Gnomad AMR exome AF: 0.194

Gnomad ASJ exome AF: 0.0298

Gnomad EAS exome AF: 0.0276

Gnomad FIN exome AF: 0.0577

Gnomad NFE exome AF: 0.0323

Gnomad OTH exome AF: 0.0591

GnomAD4 exome AF: 0.0453 AC: 66198 AN: 1461454 Hom.: 3089 Cov.: 33 AF XY: 0.0484 AC XY: 35166 AN XY: 727012

African (AFR) AF: 0.0118 AC: 396 AN: 33458

American (AMR) AF: 0.190 AC: 8503 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.0293 AC: 766 AN: 26126

East Asian (EAS) AF: 0.0138 AC: 548 AN: 39692

South Asian (SAS) AF: 0.173 AC: 14905 AN: 86252

European-Finnish (FIN) AF: 0.0588 AC: 3141 AN: 53400

Middle Eastern (MID) AF: 0.0479 AC: 276 AN: 5764

European-Non Finnish (NFE) AF: 0.0313 AC: 34773 AN: 1111696

Other (OTH) AF: 0.0479 AC: 2890 AN: 60356

GnomAD4 genome AF: 0.0445 AC: 6780 AN: 152190 Hom.: 359 Cov.: 33 AF XY: 0.0513 AC XY: 3819 AN XY: 74382

African (AFR) AF: 0.0133 AC: 554 AN: 41546

American (AMR) AF: 0.152 AC: 2323 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.0297 AC: 103 AN: 3470

East Asian (EAS) AF: 0.0240 AC: 124 AN: 5174

South Asian (SAS) AF: 0.176 AC: 847 AN: 4818

European-Finnish (FIN) AF: 0.0584 AC: 619 AN: 10602

Middle Eastern (MID) AF: 0.0612 AC: 18 AN: 294

European-Non Finnish (NFE) AF: 0.0303 AC: 2063 AN: 67998

Other (OTH) AF: 0.0398 AC: 84 AN: 2112

Alfa AF: 0.0347 Hom.: 602

Bravo AF: 0.0457

TwinsUK AF: 0.0297 AC: 110

ALSPAC AF: 0.0280 AC: 108

ESP6500AA AF: 0.0158 AC: 67

ESP6500EA AF: 0.0287 AC: 243

ExAC AF: 0.0678 AC: 8216

Asia WGS AF: 0.110 AC: 381 AN: 3478

EpiCase AF: 0.0303

EpiControl AF: 0.0312

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	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)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.57
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.14
CADD	Uncertain	24
DANN	Benign	0.97
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.94	D
MetaRNN	Benign	0.0017	T
MetaSVM	Benign	-0.47	T
MutationAssessor	Pathogenic	3.5	H
PhyloP100		7.9
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-3.7	D
REVEL	Uncertain	0.43
Sift	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.38
MPC		0.52
ClinPred		0.022	T
GERP RS		6.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
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: rs4894028; hg19: chr2-179403750; COSMIC: COSV60434767; COSMIC: COSV60434767;