rs16866538

Variant names:

• chr2-178795185-G-A
• rs16866538
• NM_001267550.2:c.982C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-178795185-G-A
• chr2-178795185-G-C
• chr2-178795185-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.982C>T​(p.Arg328Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0835 in 1,613,984 control chromosomes in the GnomAD database, including 13,306 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. R328H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.11 (1792 hom., cov: 32)
  • Exomes 𝑓: 0.081 (11514 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:23
• Conservation: PhyloP100: 5.45
• Publications: 33 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 Gene-Disease associations (from GenCC):

• dilated cardiomyopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• dilated cardiomyopathy 1G

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• early-onset myopathy with fatal cardiomyopathy

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae)
• TTN-related myopathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• myopathy, myofibrillar, 9, with early respiratory failure

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• tibial muscular dystrophy

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: ClinGen, Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• autosomal recessive limb-girdle muscular dystrophy type 2J

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• autosomal recessive centronuclear myopathy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• childhood-onset progressive contractures-limb-girdle weakness-muscle dystrophy syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• congenital myopathy

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• hereditary skeletal muscle disorder

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• hypertrophic cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• hypertrophic cardiomyopathy 9

  Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
• arrhythmogenic right ventricular cardiomyopathy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=2.1404028E-4).
• BP6: Variant 2-178795185-G-A is Benign according to our data. Variant chr2-178795185-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 47703.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.563 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.982C>T	p.Arg328Cys	missense	Exon 7 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.982C>T	p.Arg328Cys	missense	Exon 7 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.982C>T	p.Arg328Cys	missense	Exon 7 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.982C>T	p.Arg328Cys	missense	Exon 7 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.982C>T	p.Arg328Cys	missense	Exon 7 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.982C>T	p.Arg328Cys	missense	Exon 7 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.111 AC: 16910 AN: 152028 Hom.: 1794 Cov.: 32

Gnomad AFR AF: 0.167

Gnomad AMI AF: 0.127

Gnomad AMR AF: 0.0928

Gnomad ASJ AF: 0.0617

Gnomad EAS AF: 0.581

Gnomad SAS AF: 0.190

Gnomad FIN AF: 0.0535

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0525

Gnomad OTH AF: 0.0927

GnomAD2 exomes AF: 0.124 AC: 31037 AN: 250968 AF XY: 0.122

Gnomad AFR exome AF: 0.169

Gnomad AMR exome AF: 0.101

Gnomad ASJ exome AF: 0.0662

Gnomad EAS exome AF: 0.597

Gnomad FIN exome AF: 0.0489

Gnomad NFE exome AF: 0.0513

Gnomad OTH exome AF: 0.0844

GnomAD4 exome AF: 0.0806 AC: 117804 AN: 1461838 Hom.: 11514 Cov.: 33 AF XY: 0.0829 AC XY: 60293 AN XY: 727230

African (AFR) AF: 0.171 AC: 5721 AN: 33480

American (AMR) AF: 0.0997 AC: 4460 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0647 AC: 1691 AN: 26134

East Asian (EAS) AF: 0.596 AC: 23652 AN: 39696

South Asian (SAS) AF: 0.184 AC: 15872 AN: 86258

European-Finnish (FIN) AF: 0.0462 AC: 2467 AN: 53412

Middle Eastern (MID) AF: 0.0591 AC: 341 AN: 5768

European-Non Finnish (NFE) AF: 0.0518 AC: 57620 AN: 1111976

Other (OTH) AF: 0.0990 AC: 5980 AN: 60390

GnomAD4 genome AF: 0.111 AC: 16923 AN: 152146 Hom.: 1792 Cov.: 32 AF XY: 0.115 AC XY: 8559 AN XY: 74364

African (AFR) AF: 0.167 AC: 6921 AN: 41502

American (AMR) AF: 0.0929 AC: 1420 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0617 AC: 214 AN: 3470

East Asian (EAS) AF: 0.580 AC: 2992 AN: 5158

South Asian (SAS) AF: 0.190 AC: 914 AN: 4812

European-Finnish (FIN) AF: 0.0535 AC: 567 AN: 10592

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.0525 AC: 3569 AN: 68004

Other (OTH) AF: 0.0965 AC: 204 AN: 2114

Alfa AF: 0.0794 Hom.: 5017

Bravo AF: 0.119

TwinsUK AF: 0.0464 AC: 172

ALSPAC AF: 0.0514 AC: 198

ESP6500AA AF: 0.156 AC: 689

ESP6500EA AF: 0.0531 AC: 457

ExAC AF: 0.124 AC: 15044

Asia WGS AF: 0.362 AC: 1259 AN: 3478

ClinVar

ClinVar submissions

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	Uncertain	0.56
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Uncertain	0.050
CADD	Uncertain	23
DANN	Benign	0.68
Eigen	Benign	-0.13
Eigen_PC	Benign	-0.077
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.95	D
MetaRNN	Benign	0.00021	T
MetaSVM	Benign	-0.89	T
PhyloP100		5.4
PrimateAI	Uncertain	0.54	T
PROVEAN	Pathogenic	-4.6	D
REVEL	Uncertain	0.42
Sift	Uncertain	0.0070	D
Sift4G	Pathogenic	0.0010	D
Polyphen		0.14	B
Vest4		0.18
MPC		0.12
ClinPred		0.034	T
GERP RS		5.3
PromoterAI		-0.098	Neutral
Mutation Taster		=93/7	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs16866538; hg19: chr2-179659912; COSMIC: COSV60072022; COSMIC: COSV60072022;