chr2-178698879-C-A

Variant names:

• chr2-178698879-C-A
• rs111671438
• NM_001267550.2:c.30718G>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001267550.2(TTN):​c.30718G>T​(p.Val10240Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00195 in 1,526,754 control chromosomes in the GnomAD database, including 5 homozygotes. 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 0.0015 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0020 (5 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:9 B:16
• Conservation: PhyloP100: 0.960
• Publications: 6 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]

LOC124906100 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0077172816).
• BP6: Variant 2-178698879-C-A is Benign according to our data. Variant chr2-178698879-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 46841.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00147 (209/141898) while in subpopulation NFE AF = 0.00235 (155/65926). AF 95% confidence interval is 0.00205. There are 0 homozygotes in GnomAd4. There are 97 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 5 AD,AR gene

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.30718G>T	p.Val10240Phe	missense	Exon 112 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.29767G>T	p.Val9923Phe	missense	Exon 110 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.26986G>T	p.Val8996Phe	missense	Exon 109 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.30718G>T	p.Val10240Phe	missense	Exon 112 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.30718G>T	p.Val10240Phe	missense	Exon 112 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.30442G>T	p.Val10148Phe	missense	Exon 110 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.00147 AC: 209 AN: 141804 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000447

Gnomad AMI AF: 0.0168

Gnomad AMR AF: 0.000869

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000999

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00235

Gnomad OTH AF: 0.00105

GnomAD2 exomes AF: 0.000841 AC: 127 AN: 151082 AF XY: 0.000816

Gnomad AFR exome AF: 0.000618

Gnomad AMR exome AF: 0.000337

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000204

Gnomad NFE exome AF: 0.00183

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00199 AC: 2762 AN: 1384856 Hom.: 5 Cov.: 30 AF XY: 0.00191 AC XY: 1305 AN XY: 682438

African (AFR) AF: 0.000385 AC: 12 AN: 31186

American (AMR) AF: 0.000228 AC: 8 AN: 35050

Ashkenazi Jewish (ASJ) AF: 0.0000400 AC: 1 AN: 25008

East Asian (EAS) AF: 0.00 AC: 0 AN: 35704

South Asian (SAS) AF: 0.00 AC: 0 AN: 75292

European-Finnish (FIN) AF: 0.000310 AC: 14 AN: 45210

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5630

European-Non Finnish (NFE) AF: 0.00248 AC: 2659 AN: 1074246

Other (OTH) AF: 0.00118 AC: 68 AN: 57530

GnomAD4 genome AF: 0.00147 AC: 209 AN: 141898 Hom.: 0 Cov.: 31 AF XY: 0.00142 AC XY: 97 AN XY: 68460

African (AFR) AF: 0.000446 AC: 17 AN: 38134

American (AMR) AF: 0.000868 AC: 12 AN: 13826

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3400

East Asian (EAS) AF: 0.00 AC: 0 AN: 4946

South Asian (SAS) AF: 0.00 AC: 0 AN: 4566

European-Finnish (FIN) AF: 0.000999 AC: 8 AN: 8006

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 272

European-Non Finnish (NFE) AF: 0.00235 AC: 155 AN: 65926

Other (OTH) AF: 0.00104 AC: 2 AN: 1928

Alfa AF: 0.00180 Hom.: 10

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.00311 AC: 12

ESP6500AA AF: 0.000566 AC: 2

ESP6500EA AF: 0.00176 AC: 14

ExAC AF: 0.000394 AC: 39

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	6	not provided (7)
-	2	5	not specified (7)
-	2	-	Autosomal recessive limb-girdle muscular dystrophy type 2J (2)
-	2	-	Dilated cardiomyopathy 1G (2)
-	1	1	Tibial muscular dystrophy (2)
-	-	1	Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G (1)
-	1	-	Early-onset myopathy with fatal cardiomyopathy (1)
-	-	1	Hypertrophic cardiomyopathy;C0023976:Long QT syndrome;C0878544:Cardiomyopathy (1)
-	-	1	Myopathy, myofibrillar, 9, with early respiratory failure (1)
-	-	1	TTN-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	16
DANN	Uncertain	0.98
DEOGEN2	Benign	0.087	T
Eigen	Benign	-0.041
Eigen_PC	Benign	-0.055
FATHMM_MKL	Benign	0.41	N
LIST_S2	Benign	0.74	T
M_CAP	Benign	0.056	D
MetaRNN	Benign	0.0077	T
MetaSVM	Benign	-0.80	T
PhyloP100		0.96
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-2.8	D
REVEL	Benign	0.24
Sift	Uncertain	0.0080	D
Polyphen		0.43	B
Vest4		0.37
MVP		0.64
MPC		0.15
ClinPred		0.024	T
GERP RS		3.7
Mutation Taster		=83/17	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: rs111671438; hg19: chr2-179563606;