chr2-178735577-T-G

Variant names:

• chr2-178735577-T-G
• rs780405420
• NM_001267550.2:c.14869A>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4 BP6

The NM_001267550.2(TTN):​c.14869A>C​(p.Thr4957Pro) variant causes a missense change. The variant allele was found at a frequency of 0.0000936 in 1,612,908 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. T4957S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000089 (0 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:3
• Conservation: PhyloP100: 5.07
• 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 -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.28702188).
• BP6: Variant 2-178735577-T-G is Benign according to our data. Variant chr2-178735577-T-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 192033.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	NM_001267550.2	MANE Select	c.14869A>C	p.Thr4957Pro	missense	Exon 50 of 363	NP_001254479.2
	TTN	NM_001256850.1		c.13918A>C	p.Thr4640Pro	missense	Exon 48 of 313	NP_001243779.1
	TTN	NM_133378.4		c.11137A>C	p.Thr3713Pro	missense	Exon 47 of 312	NP_596869.4

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	ENST00000589042.5	TSL:5 MANE Select	c.14869A>C	p.Thr4957Pro	missense	Exon 50 of 363	ENSP00000467141.1
	TTN	ENST00000446966.2	TSL:1	c.14869A>C	p.Thr4957Pro	missense	Exon 50 of 361	ENSP00000408004.2
	TTN	ENST00000436599.2	TSL:1	c.14593A>C	p.Thr4865Pro	missense	Exon 48 of 361	ENSP00000405517.2

Frequencies

GnomAD3 genomes AF: 0.000138 AC: 21 AN: 152180 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000889 AC: 22 AN: 247504 AF XY: 0.0000819

Gnomad AFR exome AF: 0.0000648

Gnomad AMR exome AF: 0.000146

Gnomad ASJ exome AF: 0.000299

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000116

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000890 AC: 130 AN: 1460728 Hom.: 0 Cov.: 29 AF XY: 0.0000950 AC XY: 69 AN XY: 726614

African (AFR) AF: 0.0000300 AC: 1 AN: 33380

American (AMR) AF: 0.000224 AC: 10 AN: 44604

Ashkenazi Jewish (ASJ) AF: 0.000115 AC: 3 AN: 26100

East Asian (EAS) AF: 0.00 AC: 0 AN: 39580

South Asian (SAS) AF: 0.00 AC: 0 AN: 86106

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53318

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

European-Non Finnish (NFE) AF: 0.000101 AC: 112 AN: 1111580

Other (OTH) AF: 0.0000663 AC: 4 AN: 60300

GnomAD4 genome AF: 0.000138 AC: 21 AN: 152180 Hom.: 0 Cov.: 33 AF XY: 0.0000942 AC XY: 7 AN XY: 74348

African (AFR) AF: 0.00 AC: 0 AN: 41456

American (AMR) AF: 0.000197 AC: 3 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

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: 0.000250 AC: 17 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000183 Hom.: 0

Bravo AF: 0.0000945

ExAC AF: 0.0000745 AC: 9

EpiCase AF: 0.0000545

EpiControl AF: 0.000416

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	2	not provided (4)
-	1	1	not specified (2)
-	1	-	Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G (1)
-	1	-	Dilated cardiomyopathy 1G;C1861065:Hypertrophic cardiomyopathy 9 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.10
CADD	Benign	21
DANN	Benign	0.93
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.63	T
M_CAP	Benign	0.081	D
MetaRNN	Benign	0.29	T
MetaSVM	Uncertain	-0.25	T
PhyloP100		5.1
PrimateAI	Benign	0.30	T
PROVEAN	Uncertain	-2.8	D
REVEL	Uncertain	0.33
Sift	Benign	0.24	T
Polyphen		0.30	B
Vest4		0.24
MVP		0.47
MPC		0.22
ClinPred		0.085	T
GERP RS		5.8
Mutation Taster		=83/17	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: rs780405420; hg19: chr2-179600304;