rs1001238

Variant names:

• chr2-178599800-T-C
• rs1001238
• NM_001267550.2:c.56101A>G

Your query was ambiguous. Multiple possible variants found:

• chr2-178599800-T-C
• chr2-178599800-T-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.56101A>G​(p.Asn18701Asp) variant causes a missense change. The variant allele was found at a frequency of 0.279 in 1,607,130 control chromosomes in the GnomAD database, including 75,371 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.36 (11911 hom., cov: 32)
  • Exomes 𝑓: 0.27 (63460 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:22
• Conservation: PhyloP100: 6.13
• Publications: 48 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=1.4161484E-5).
• BP6: Variant 2-178599800-T-C is Benign according to our data. Variant chr2-178599800-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 47110.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.69 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.56101A>G	p.Asn18701Asp	missense	Exon 289 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.51178A>G	p.Asn17060Asp	missense	Exon 239 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.48397A>G	p.Asn16133Asp	missense	Exon 238 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.56101A>G	p.Asn18701Asp	missense	Exon 289 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.55945A>G	p.Asn18649Asp	missense	Exon 287 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.55825A>G	p.Asn18609Asp	missense	Exon 287 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.363 AC: 55096 AN: 151738 Hom.: 11862 Cov.: 32

Gnomad AFR AF: 0.540

Gnomad AMI AF: 0.559

Gnomad AMR AF: 0.387

Gnomad ASJ AF: 0.291

Gnomad EAS AF: 0.709

Gnomad SAS AF: 0.521

Gnomad FIN AF: 0.287

Gnomad MID AF: 0.282

Gnomad NFE AF: 0.227

Gnomad OTH AF: 0.331

GnomAD2 exomes AF: 0.355 AC: 86524 AN: 243536 AF XY: 0.352

Gnomad AFR exome AF: 0.544

Gnomad AMR exome AF: 0.432

Gnomad ASJ exome AF: 0.290

Gnomad EAS exome AF: 0.713

Gnomad FIN exome AF: 0.279

Gnomad NFE exome AF: 0.228

Gnomad OTH exome AF: 0.311

GnomAD4 exome AF: 0.270 AC: 393045 AN: 1455274 Hom.: 63460 Cov.: 35 AF XY: 0.275 AC XY: 199194 AN XY: 723532

African (AFR) AF: 0.554 AC: 18336 AN: 33082

American (AMR) AF: 0.429 AC: 18809 AN: 43808

Ashkenazi Jewish (ASJ) AF: 0.288 AC: 7476 AN: 25948

East Asian (EAS) AF: 0.701 AC: 27642 AN: 39408

South Asian (SAS) AF: 0.510 AC: 43292 AN: 84962

European-Finnish (FIN) AF: 0.279 AC: 14812 AN: 53164

Middle Eastern (MID) AF: 0.317 AC: 1818 AN: 5736

European-Non Finnish (NFE) AF: 0.219 AC: 242515 AN: 1109068

Other (OTH) AF: 0.305 AC: 18345 AN: 60098

GnomAD4 genome AF: 0.364 AC: 55207 AN: 151856 Hom.: 11911 Cov.: 32 AF XY: 0.374 AC XY: 27732 AN XY: 74194

African (AFR) AF: 0.541 AC: 22404 AN: 41416

American (AMR) AF: 0.388 AC: 5911 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.291 AC: 1009 AN: 3472

East Asian (EAS) AF: 0.709 AC: 3619 AN: 5104

South Asian (SAS) AF: 0.519 AC: 2500 AN: 4816

European-Finnish (FIN) AF: 0.287 AC: 3037 AN: 10570

Middle Eastern (MID) AF: 0.289 AC: 85 AN: 294

European-Non Finnish (NFE) AF: 0.227 AC: 15420 AN: 67918

Other (OTH) AF: 0.339 AC: 713 AN: 2104

Alfa AF: 0.283 Hom.: 23052

Bravo AF: 0.377

TwinsUK AF: 0.214 AC: 794

ALSPAC AF: 0.216 AC: 834

ESP6500AA AF: 0.533 AC: 1980

ESP6500EA AF: 0.226 AC: 1846

ExAC AF: 0.353 AC: 42659

Asia WGS AF: 0.622 AC: 2161 AN: 3476

EpiCase AF: 0.223

EpiControl AF: 0.232

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	0.052
BayesDel_addAF	Benign	-0.74	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	21
DANN	Benign	0.93
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.11
FATHMM_MKL	Benign	0.044	N
LIST_S2	Benign	0.49	T
MetaRNN	Benign	0.000014	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-0.52	N
PhyloP100		6.1
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	2.8	N
REVEL	Benign	0.16
Sift	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.035
MPC		0.095
ClinPred		0.011	T
GERP RS		5.6
Mutation Taster		=96/4	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs1001238; hg19: chr2-179464527; COSMIC: COSV60287713; COSMIC: COSV60287713;