chr2-178693979-T-A

Variant names:

• chr2-178693979-T-A
• rs772882862
• NM_001267550.2:c.31456A>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.31456A>T​(p.Ile10486Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000608 in 1,612,438 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/19 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 0.000059 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000061 (0 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8 B:3
• Conservation: PhyloP100: -0.0920
• Publications: 0 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]

LOC124907912 (HGNC:):

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=0.09404582).
• BP6: Variant 2-178693979-T-A is Benign according to our data. Variant chr2-178693979-T-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 332894.

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.31456A>T	p.Ile10486Phe	missense	Exon 118 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.30505A>T	p.Ile10169Phe	missense	Exon 116 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.27724A>T	p.Ile9242Phe	missense	Exon 115 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.31456A>T	p.Ile10486Phe	missense	Exon 118 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.31456A>T	p.Ile10486Phe	missense	Exon 118 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.31180A>T	p.Ile10394Phe	missense	Exon 116 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.0000591 AC: 9 AN: 152208 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

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: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000485 AC: 12 AN: 247582 AF XY: 0.0000596

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: 0.0000930

Gnomad NFE exome AF: 0.0000802

Gnomad OTH exome AF: 0.000167

GnomAD4 exome AF: 0.0000609 AC: 89 AN: 1460230 Hom.: 0 Cov.: 30 AF XY: 0.0000647 AC XY: 47 AN XY: 726304

African (AFR) AF: 0.00 AC: 0 AN: 33448

American (AMR) AF: 0.00 AC: 0 AN: 44544

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26094

East Asian (EAS) AF: 0.00 AC: 0 AN: 39656

South Asian (SAS) AF: 0.00 AC: 0 AN: 85956

European-Finnish (FIN) AF: 0.0000937 AC: 5 AN: 53354

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.0000747 AC: 83 AN: 1111112

Other (OTH) AF: 0.0000166 AC: 1 AN: 60304

GnomAD4 genome AF: 0.0000591 AC: 9 AN: 152208 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74358

African (AFR) AF: 0.0000241 AC: 1 AN: 41462

American (AMR) AF: 0.00 AC: 0 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

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

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10618

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

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 68030

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

Alfa AF: 0.000184 Hom.: 0

Bravo AF: 0.0000378

ExAC AF: 0.0000745 AC: 9

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	1	not provided (3)
-	2	-	Autosomal recessive limb-girdle muscular dystrophy type 2J (2)
-	2	-	Dilated cardiomyopathy 1G (2)
-	1	1	Tibial muscular dystrophy (2)
-	1	-	Early-onset myopathy with fatal cardiomyopathy (1)
-	-	1	Myopathy, myofibrillar, 9, with early respiratory failure (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	15
DANN	Uncertain	0.98
DEOGEN2	Benign	0.038	T
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.14
FATHMM_MKL	Benign	0.61	D
LIST_S2	Benign	0.62	T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.094	T
MetaSVM	Benign	-0.99	T
PhyloP100		-0.092
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.097
Sift	Uncertain	0.010	D
Polyphen		0.077	B
Vest4		0.30
MVP		0.34
MPC		0.14
ClinPred		0.074	T
GERP RS		2.1
Mutation Taster		=45/55	disease causing

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: rs772882862; hg19: chr2-179558706;