2-178620299-C-T

Variant names:

• chr2-178620299-C-T
• rs730880239
• NM_001267550.2:c.46222G>A

Variant summary

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

The NM_001267550.2(TTN):​c.46222G>A​(p.Ala15408Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000824 in 1,564,988 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).

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000085 (0 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 7.86
• Publications: 7 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=0.2959968).
• BP6: Variant 2-178620299-C-T is Benign according to our data. Variant chr2-178620299-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 180568.

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.46222G>A	p.Ala15408Thr	missense	Exon 248 of 363	NP_001254479.2
	TTN	NM_001256850.1		c.41299G>A	p.Ala13767Thr	missense	Exon 198 of 313	NP_001243779.1
	TTN	NM_133378.4		c.38518G>A	p.Ala12840Thr	missense	Exon 197 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.46222G>A	p.Ala15408Thr	missense	Exon 248 of 363	ENSP00000467141.1
	TTN	ENST00000446966.2	TSL:1	c.46066G>A	p.Ala15356Thr	missense	Exon 246 of 361	ENSP00000408004.2
	TTN	ENST00000436599.2	TSL:1	c.45946G>A	p.Ala15316Thr	missense	Exon 246 of 361	ENSP00000405517.2

Frequencies

GnomAD3 genomes AF: 0.0000593 AC: 9 AN: 151882 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000657

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000884

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000169 AC: 36 AN: 213040 AF XY: 0.000176

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000134

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000581

Gnomad FIN exome AF: 0.000416

Gnomad NFE exome AF: 0.000202

Gnomad OTH exome AF: 0.000599

GnomAD4 exome AF: 0.0000849 AC: 120 AN: 1413106 Hom.: 0 Cov.: 32 AF XY: 0.0000804 AC XY: 56 AN XY: 696750

African (AFR) AF: 0.00 AC: 0 AN: 32002

American (AMR) AF: 0.000101 AC: 4 AN: 39624

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22974

East Asian (EAS) AF: 0.0000255 AC: 1 AN: 39140

South Asian (SAS) AF: 0.00 AC: 0 AN: 76590

European-Finnish (FIN) AF: 0.000621 AC: 32 AN: 51548

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5484

European-Non Finnish (NFE) AF: 0.0000717 AC: 78 AN: 1087568

Other (OTH) AF: 0.0000859 AC: 5 AN: 58176

GnomAD4 genome AF: 0.0000593 AC: 9 AN: 151882 Hom.: 0 Cov.: 32 AF XY: 0.0000539 AC XY: 4 AN XY: 74164

African (AFR) AF: 0.00 AC: 0 AN: 41400

American (AMR) AF: 0.0000657 AC: 1 AN: 15220

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5146

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10616

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

European-Non Finnish (NFE) AF: 0.0000884 AC: 6 AN: 67890

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000378

ExAC AF: 0.000199 AC: 24

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.71
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.090
CADD	Uncertain	24
DANN	Benign	0.96
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.30	T
MetaSVM	Uncertain	0.28	D
MutationAssessor	Uncertain	2.9	M
PhyloP100		7.9
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-2.8	D
REVEL	Uncertain	0.61
Sift	Uncertain	0.0080	D
Polyphen		1.0	D
Vest4		0.52
MVP		0.67
MPC		0.46
ClinPred		0.14	T
GERP RS		5.9
Mutation Taster		=73/27	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: rs730880239; hg19: chr2-179485026; COSMIC: COSV59920173; COSMIC: COSV59920173;