rs375944265

Variant names:

• chr2-178607860-G-A
• rs375944265
• NM_001267550.2:c.52927C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-178607860-G-A
• chr2-178607860-G-T

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.52927C>T​(p.Arg17643Trp) variant causes a missense change. The variant allele was found at a frequency of 0.0000533 in 1,613,036 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. R17643L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00030 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000028 (0 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:3
• Conservation: PhyloP100: 3.73
• Publications: 2 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=0.08143601).
• BP6: Variant 2-178607860-G-A is Benign according to our data. Variant chr2-178607860-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 229459.

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.52927C>T	p.Arg17643Trp	missense	Exon 276 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.48004C>T	p.Arg16002Trp	missense	Exon 226 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.45223C>T	p.Arg15075Trp	missense	Exon 225 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.52927C>T	p.Arg17643Trp	missense	Exon 276 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.52771C>T	p.Arg17591Trp	missense	Exon 274 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.52651C>T	p.Arg17551Trp	missense	Exon 274 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.000296 AC: 45 AN: 151984 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000772

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000459

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000583

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.0000604 AC: 15 AN: 248394 AF XY: 0.0000668

Gnomad AFR exome AF: 0.000776

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000562

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000281 AC: 41 AN: 1460934 Hom.: 0 Cov.: 32 AF XY: 0.0000234 AC XY: 17 AN XY: 726782

African (AFR) AF: 0.000419 AC: 14 AN: 33420

American (AMR) AF: 0.0000447 AC: 2 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26118

East Asian (EAS) AF: 0.00 AC: 0 AN: 39560

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86240

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53398

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.0000180 AC: 20 AN: 1111412

Other (OTH) AF: 0.0000663 AC: 4 AN: 60326

GnomAD4 genome AF: 0.000296 AC: 45 AN: 152102 Hom.: 0 Cov.: 32 AF XY: 0.000296 AC XY: 22 AN XY: 74334

African (AFR) AF: 0.000770 AC: 32 AN: 41562

American (AMR) AF: 0.000459 AC: 7 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.000585 AC: 3 AN: 5130

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

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

European-Non Finnish (NFE) AF: 0.0000295 AC: 2 AN: 67908

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.000183 Hom.: 0

Bravo AF: 0.000276

ESP6500AA AF: 0.000505 AC: 2

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000744 AC: 9

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not provided (2)
-	1	1	not specified (2)
-	-	1	Cardiovascular phenotype (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.48
BayesDel_addAF	Benign	-0.074	T
BayesDel_noAF	Uncertain	0.020
CADD	Benign	23
DANN	Benign	0.96
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.053	D
MetaRNN	Benign	0.081	T
MetaSVM	Uncertain	0.40	D
MutationAssessor	Pathogenic	3.7	H
PhyloP100		3.7
PrimateAI	Uncertain	0.69	T
PROVEAN	Pathogenic	-6.2	D
REVEL	Uncertain	0.45
Sift	Uncertain	0.0010	D
Polyphen		1.0	D
Vest4		0.46
MVP		0.60
MPC		0.47
ClinPred		0.35	T
GERP RS		6.1
Mutation Taster		=82/18	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: rs375944265; hg19: chr2-179472587; COSMIC: COSV60285827; COSMIC: COSV60285827;