rs187703540

Variant names:

• chr2-178759124-C-T
• rs187703540
• NM_001267550.2:c.10163G>A

Your query was ambiguous. Multiple possible variants found:

• chr2-178759124-C-T
• chr2-178759124-C-A
• chr2-178759124-C-G

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_001267550.2(TTN):​c.10163G>A​(p.Arg3388Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000217 in 1,613,916 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R3388W) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00051 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00019 (0 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:10
• Conservation: PhyloP100: 4.05
• Publications: 5 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0058184266).
• BP6: Variant 2-178759124-C-T is Benign according to our data. Variant chr2-178759124-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 137831.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000513 (78/152194) while in subpopulation EAS AF = 0.012 (62/5178). AF 95% confidence interval is 0.00959. There are 0 homozygotes in GnomAd4. There are 45 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

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.10163G>A	p.Arg3388Gln	missense	Exon 44 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.10163G>A	p.Arg3388Gln	missense	Exon 44 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.10163G>A	p.Arg3388Gln	missense	Exon 44 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.10163G>A	p.Arg3388Gln	missense	Exon 44 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.10163G>A	p.Arg3388Gln	missense	Exon 44 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.9887G>A	p.Arg3296Gln	missense	Exon 42 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.000513 AC: 78 AN: 152076 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000266

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0119

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000746 AC: 187 AN: 250542 AF XY: 0.000746

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00932

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000187 AC: 273 AN: 1461722 Hom.: 0 Cov.: 39 AF XY: 0.000213 AC XY: 155 AN XY: 727160

African (AFR) AF: 0.000239 AC: 8 AN: 33478

American (AMR) AF: 0.0000447 AC: 2 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00545 AC: 216 AN: 39664

South Asian (SAS) AF: 0.000197 AC: 17 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53406

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1111926

Other (OTH) AF: 0.000414 AC: 25 AN: 60390

GnomAD4 genome AF: 0.000513 AC: 78 AN: 152194 Hom.: 0 Cov.: 33 AF XY: 0.000605 AC XY: 45 AN XY: 74406

African (AFR) AF: 0.000265 AC: 11 AN: 41526

American (AMR) AF: 0.00 AC: 0 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.0120 AC: 62 AN: 5178

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10594

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68008

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.000190 Hom.: 1

Bravo AF: 0.000408

ExAC AF: 0.000667 AC: 81

Asia WGS AF: 0.00722 AC: 25 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not provided (2)
-	-	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	Cardiomyopathy (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Dilated cardiomyopathy 1G (1)
-	1	-	Early-onset myopathy with fatal cardiomyopathy (1)
-	-	1	Hypertrophic 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
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.26
CADD	Uncertain	25
DANN	Uncertain	0.99
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.97	D
MetaRNN	Benign	0.0058	T
MetaSVM	Benign	-0.72	T
PhyloP100		4.0
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.18
Sift	Benign	0.56	T
Sift4G	Uncertain	0.049	D
Polyphen		0.91	P
Vest4		0.32
MVP		0.23
MPC		0.18
ClinPred		0.028	T
GERP RS		5.9
Mutation Taster		=84/16	polymorphism

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: rs187703540; hg19: chr2-179623851;