rs200941841

Variant names:

• chr2-178733085-C-T
• rs200941841
• NM_001267550.2:c.16091G>A

Your query was ambiguous. Multiple possible variants found:

• chr2-178733085-C-T
• chr2-178733085-C-A

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_Moderate BP6

The NM_001267550.2(TTN):​c.16091G>A​(p.Arg5364His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000717 in 1,603,196 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict 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. R5364C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000066 (0 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:3
• Conservation: PhyloP100: 3.25
• 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: Likely_benign. The variant received -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.15047881).
• BP6: Variant 2-178733085-C-T is Benign according to our data. Variant chr2-178733085-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 178256.

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.16091G>A	p.Arg5364His	missense	Exon 55 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.15140G>A	p.Arg5047His	missense	Exon 53 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.12359G>A	p.Arg4120His	missense	Exon 52 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.16091G>A	p.Arg5364His	missense	Exon 55 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.16091G>A	p.Arg5364His	missense	Exon 55 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.15815G>A	p.Arg5272His	missense	Exon 53 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.000125 AC: 19 AN: 152126 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00116

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000137 AC: 33 AN: 241404 AF XY: 0.000107

Gnomad AFR exome AF: 0.000195

Gnomad AMR exome AF: 0.0000597

Gnomad ASJ exome AF: 0.000534

Gnomad EAS exome AF: 0.000562

Gnomad FIN exome AF: 0.0000474

Gnomad NFE exome AF: 0.000100

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000662 AC: 96 AN: 1450952 Hom.: 0 Cov.: 36 AF XY: 0.0000569 AC XY: 41 AN XY: 720334

African (AFR) AF: 0.0000603 AC: 2 AN: 33154

American (AMR) AF: 0.000182 AC: 8 AN: 43884

Ashkenazi Jewish (ASJ) AF: 0.000469 AC: 12 AN: 25572

East Asian (EAS) AF: 0.000330 AC: 13 AN: 39450

South Asian (SAS) AF: 0.0000354 AC: 3 AN: 84794

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53116

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5716

European-Non Finnish (NFE) AF: 0.0000407 AC: 45 AN: 1105420

Other (OTH) AF: 0.000201 AC: 12 AN: 59846

GnomAD4 genome AF: 0.000125 AC: 19 AN: 152244 Hom.: 0 Cov.: 33 AF XY: 0.000134 AC XY: 10 AN XY: 74426

African (AFR) AF: 0.0000963 AC: 4 AN: 41556

American (AMR) AF: 0.000131 AC: 2 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3472

East Asian (EAS) AF: 0.00116 AC: 6 AN: 5168

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

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

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68018

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000127 Hom.: 0

Bravo AF: 0.000193

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.000258 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000149 AC: 18

Asia WGS AF: 0.000289 AC: 1 AN: 3476

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	4	1	not provided (5)
-	-	1	Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G (1)
-	-	1	Cardiomyopathy (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	22
DANN	Benign	0.92
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.038	D
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-0.33	T
PhyloP100		3.3
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-2.7	D
REVEL	Uncertain	0.40
Sift	Benign	0.056	T
Polyphen		0.98	D
Vest4		0.36
MVP		0.39
MPC		0.31
ClinPred		0.065	T
GERP RS		5.3
Mutation Taster		=93/7	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs200941841; hg19: chr2-179597812; COSMIC: COSV60055171; COSMIC: COSV60055171;