rs376465623

Variant names:

• chr2-178592531-C-G
• rs376465623
• NM_001267550.2:c.59474G>C

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.59474G>C​(p.Arg19825Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000102 in 1,613,400 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/20 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 0.000053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:4
• Conservation: PhyloP100: 1.61
• Publications: 1 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=0.10379258).
• BP6: Variant 2-178592531-C-G is Benign according to our data. Variant chr2-178592531-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 467328.

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.59474G>C	p.Arg19825Thr	missense	Exon 301 of 363	NP_001254479.2
	TTN	NM_001256850.1		c.54551G>C	p.Arg18184Thr	missense	Exon 251 of 313	NP_001243779.1
	TTN	NM_133378.4		c.51770G>C	p.Arg17257Thr	missense	Exon 250 of 312	NP_596869.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	ENST00000589042.5	TSL:5 MANE Select	c.59474G>C	p.Arg19825Thr	missense	Exon 301 of 363	ENSP00000467141.1
	TTN	ENST00000446966.2	TSL:1	c.59318G>C	p.Arg19773Thr	missense	Exon 299 of 361	ENSP00000408004.2
	TTN	ENST00000436599.2	TSL:1	c.59198G>C	p.Arg19733Thr	missense	Exon 299 of 361	ENSP00000405517.2

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152076 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000736

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000644 AC: 16 AN: 248454 AF XY: 0.0000520

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000464

Gnomad NFE exome AF: 0.000125

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.000107 AC: 157 AN: 1461324 Hom.: 0 Cov.: 35 AF XY: 0.0000990 AC XY: 72 AN XY: 726952

African (AFR) AF: 0.0000299 AC: 1 AN: 33450

American (AMR) AF: 0.00 AC: 0 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39664

South Asian (SAS) AF: 0.00 AC: 0 AN: 86238

European-Finnish (FIN) AF: 0.0000375 AC: 2 AN: 53400

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

European-Non Finnish (NFE) AF: 0.000131 AC: 146 AN: 1111620

Other (OTH) AF: 0.000133 AC: 8 AN: 60356

GnomAD4 genome AF: 0.0000526 AC: 8 AN: 152076 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74276

African (AFR) AF: 0.0000724 AC: 3 AN: 41442

American (AMR) AF: 0.00 AC: 0 AN: 15258

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5162

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000736 AC: 5 AN: 67978

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.000141 Hom.: 0

Bravo AF: 0.0000756

ESP6500AA AF: 0.000263 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000662 AC: 8

EpiCase AF: 0.000164

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	19
DANN	Benign	0.83
Eigen	Benign	-0.052
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.041	D
MetaRNN	Benign	0.10	T
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	0.68	N
PhyloP100		1.6
PrimateAI	Benign	0.44	T
PROVEAN	Uncertain	-3.3	D
REVEL	Benign	0.10
Sift	Benign	0.41	T
Polyphen		0.081	B
Vest4		0.30
MVP		0.29
MPC		0.15
ClinPred		0.052	T
GERP RS		5.2
Mutation Taster		=79/21	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: rs376465623; hg19: chr2-179457258;