rs200021871

Variant names:

• chr2-178658787-T-A
• rs200021871
• NM_001267550.2:c.37461A>T

Your query was ambiguous. Multiple possible variants found:

• chr2-178658787-T-A
• chr2-178658787-T-C

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001267550.2(TTN):​c.37461A>T​(p.Glu12487Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 11/14 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. E12487E) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.020 (2 hom., cov: 19)
  • Exomes 𝑓: 0.023 (96 hom.)
  • Failed GnomAD Quality Control
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -1.60
• Publications: 7 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]

LOC124906100 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.001691848).
• BP6: Variant 2-178658787-T-A is Benign according to our data. Variant chr2-178658787-T-A is described in ClinVar as Benign. ClinVar VariationId is 192213.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 2 AD,AR gene

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.37461A>T	p.Glu12487Asp	missense	Exon 183 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.34522+218A>T		intron	N/A	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.31741+218A>T		intron	N/A	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.37461A>T	p.Glu12487Asp	missense	Exon 183 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.37461A>T	p.Glu12487Asp	missense	Exon 183 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.37185A>T	p.Glu12395Asp	missense	Exon 181 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.0197 AC: 2899 AN: 147482 Hom.: 2 Cov.: 19

Gnomad AFR AF: 0.00414

Gnomad AMI AF: 0.0253

Gnomad AMR AF: 0.0198

Gnomad ASJ AF: 0.0171

Gnomad EAS AF: 0.0730

Gnomad SAS AF: 0.0243

Gnomad FIN AF: 0.0394

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0220

Gnomad OTH AF: 0.0188

GnomAD2 exomes AF: 0.0268 AC: 6498 AN: 242278 AF XY: 0.0261

Gnomad AFR exome AF: 0.00416

Gnomad AMR exome AF: 0.0285

Gnomad ASJ exome AF: 0.0130

Gnomad EAS exome AF: 0.0725

Gnomad FIN exome AF: 0.0421

Gnomad NFE exome AF: 0.0219

Gnomad OTH exome AF: 0.0263

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0228 AC: 33001 AN: 1447754 Hom.: 96 Cov.: 31 AF XY: 0.0229 AC XY: 16523 AN XY: 720288

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00402 AC: 134 AN: 33312

American (AMR) AF: 0.0283 AC: 1252 AN: 44208

Ashkenazi Jewish (ASJ) AF: 0.0140 AC: 363 AN: 25940

East Asian (EAS) AF: 0.0760 AC: 2952 AN: 38848

South Asian (SAS) AF: 0.0227 AC: 1935 AN: 85394

European-Finnish (FIN) AF: 0.0448 AC: 2370 AN: 52864

Middle Eastern (MID) AF: 0.0136 AC: 56 AN: 4106

European-Non Finnish (NFE) AF: 0.0205 AC: 22585 AN: 1103410

Other (OTH) AF: 0.0227 AC: 1354 AN: 59672

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0196 AC: 2900 AN: 147606 Hom.: 2 Cov.: 19 AF XY: 0.0203 AC XY: 1460 AN XY: 71862

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00413 AC: 167 AN: 40470

American (AMR) AF: 0.0197 AC: 289 AN: 14642

Ashkenazi Jewish (ASJ) AF: 0.0171 AC: 58 AN: 3394

East Asian (EAS) AF: 0.0734 AC: 360 AN: 4904

South Asian (SAS) AF: 0.0243 AC: 109 AN: 4480

European-Finnish (FIN) AF: 0.0394 AC: 396 AN: 10062

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0220 AC: 1459 AN: 66448

Other (OTH) AF: 0.0186 AC: 38 AN: 2042

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0198 Hom.: 2

ESP6500AA AF: 0.00514 AC: 9

ESP6500EA AF: 0.0151 AC: 60

ExAC AF: 0.0303 AC: 3648

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	2	not specified (2)
-	-	1	Autosomal recessive limb-girdle muscular dystrophy type 2J (1)
-	-	1	Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G (1)
-	-	1	Early-onset myopathy with fatal cardiomyopathy (1)
-	-	1	Myopathy, myofibrillar, 9, with early respiratory failure (1)
-	-	1	Tibial muscular dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	6.9
DANN	Benign	0.87
Eigen	Benign	-0.70
Eigen_PC	Benign	-0.81
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.27	T
MetaRNN	Benign	0.0017	T
MetaSVM	Benign	-1.0	T
PhyloP100		-1.6
Vest4		0.099
MPC		0.13
ClinPred		0.0053	T
GERP RS		-1.0
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs200021871; hg19: chr2-179523514; COSMIC: COSV99045616; COSMIC: COSV99045616;