rs200513156

Variant names:

• chr2-178664032-T-C
• rs200513156
• NM_001267550.2:c.36347A>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001267550.2(TTN):​c.36347A>G​(p.Glu12116Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00313 in 1,613,386 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/15 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0021 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0032 (13 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:17
• Conservation: PhyloP100: 0.496
• Publications: 4 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006957084).
• BP6: Variant 2-178664032-T-C is Benign according to our data. Variant chr2-178664032-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 192216.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00206 (313/152278) while in subpopulation NFE AF = 0.00379 (258/68008). AF 95% confidence interval is 0.00341. There are 0 homozygotes in GnomAd4. There are 117 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 13 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.36347A>G	p.Glu12116Gly	missense	Exon 169 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.34265-977A>G		intron	N/A	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.31484-977A>G		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.36347A>G	p.Glu12116Gly	missense	Exon 169 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.36347A>G	p.Glu12116Gly	missense	Exon 169 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.36071A>G	p.Glu12024Gly	missense	Exon 167 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.00206 AC: 313 AN: 152160 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000772

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.000525

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000565

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00379

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00190 AC: 463 AN: 244288 AF XY: 0.00188

Gnomad AFR exome AF: 0.000829

Gnomad AMR exome AF: 0.000291

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000557

Gnomad NFE exome AF: 0.00377

Gnomad OTH exome AF: 0.00134

GnomAD4 exome AF: 0.00325 AC: 4743 AN: 1461108 Hom.: 13 Cov.: 33 AF XY: 0.00317 AC XY: 2303 AN XY: 726820

African (AFR) AF: 0.000448 AC: 15 AN: 33470

American (AMR) AF: 0.000380 AC: 17 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.000255 AC: 22 AN: 86248

European-Finnish (FIN) AF: 0.000679 AC: 36 AN: 52994

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5768

European-Non Finnish (NFE) AF: 0.00403 AC: 4482 AN: 1111750

Other (OTH) AF: 0.00277 AC: 167 AN: 60362

GnomAD4 genome AF: 0.00206 AC: 313 AN: 152278 Hom.: 0 Cov.: 31 AF XY: 0.00157 AC XY: 117 AN XY: 74462

African (AFR) AF: 0.000770 AC: 32 AN: 41580

American (AMR) AF: 0.000524 AC: 8 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.000565 AC: 6 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00379 AC: 258 AN: 68008

Other (OTH) AF: 0.00189 AC: 4 AN: 2116

Alfa AF: 0.00230 Hom.: 1

Bravo AF: 0.00207

TwinsUK AF: 0.00243 AC: 9

ALSPAC AF: 0.00415 AC: 16

ESP6500AA AF: 0.000571 AC: 1

ESP6500EA AF: 0.00402 AC: 16

ExAC AF: 0.00202 AC: 240

EpiCase AF: 0.00349

EpiControl AF: 0.00284

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	5	not specified (5)
-	-	1	Autosomal recessive limb-girdle muscular dystrophy type 2J (1)
-	-	1	Autosomal recessive limb-girdle muscular dystrophy type 2J;C1838244:Tibial muscular dystrophy;C1858763:Dilated cardiomyopathy 1G;C1861065:Hypertrophic cardiomyopathy 9;C1863599:Myopathy, myofibrillar, 9, with early respiratory failure;C2673677:Early-onset myopathy with fatal cardiomyopathy (1)
-	-	1	Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G (1)
-	1	-	Congenital myopathy (1)
-	-	1	Early-onset myopathy with fatal cardiomyopathy (1)
-	-	1	Myopathy, myofibrillar, 9, with early respiratory failure (1)
-	-	1	Tibial muscular dystrophy (1)
-	-	1	TTN-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	13
DANN	Uncertain	0.98
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.71
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.0070	T
MetaSVM	Benign	-1.0	T
PhyloP100		0.50
Vest4		0.13
MVP		0.42
MPC		0.11
ClinPred		0.0017	T
GERP RS		3.0
Mutation Taster		=82/18	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: rs200513156; hg19: chr2-179528759; COSMIC: COSV108177754;