chr2-178609306-C-T

Variant names:

• chr2-178609306-C-T
• rs367603302
• NM_001267550.2:c.52004G>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_001267550.2(TTN):​c.52004G>A​(p.Arg17335His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000866 in 1,605,200 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R17335C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00017 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000078 (0 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:4
• Conservation: PhyloP100: 2.89
• Publications: 4 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 -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.062913775).
• BP6: Variant 2-178609306-C-T is Benign according to our data. Variant chr2-178609306-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 195710.

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.52004G>A	p.Arg17335His	missense	Exon 273 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.47081G>A	p.Arg15694His	missense	Exon 223 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.44300G>A	p.Arg14767His	missense	Exon 222 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.52004G>A	p.Arg17335His	missense	Exon 273 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.51848G>A	p.Arg17283His	missense	Exon 271 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.51728G>A	p.Arg17243His	missense	Exon 271 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.000171 AC: 26 AN: 151920 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000442

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000116 AC: 28 AN: 242384 AF XY: 0.0000685

Gnomad AFR exome AF: 0.000391

Gnomad AMR exome AF: 0.000119

Gnomad ASJ exome AF: 0.00115

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000182

Gnomad OTH exome AF: 0.000681

GnomAD4 exome AF: 0.0000778 AC: 113 AN: 1453280 Hom.: 0 Cov.: 32 AF XY: 0.0000748 AC XY: 54 AN XY: 722356

African (AFR) AF: 0.000272 AC: 9 AN: 33030

American (AMR) AF: 0.000114 AC: 5 AN: 43874

Ashkenazi Jewish (ASJ) AF: 0.00113 AC: 29 AN: 25666

East Asian (EAS) AF: 0.00 AC: 0 AN: 39398

South Asian (SAS) AF: 0.0000236 AC: 2 AN: 84846

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53054

Middle Eastern (MID) AF: 0.000349 AC: 2 AN: 5724

European-Non Finnish (NFE) AF: 0.0000542 AC: 60 AN: 1107700

Other (OTH) AF: 0.000100 AC: 6 AN: 59988

GnomAD4 genome AF: 0.000171 AC: 26 AN: 151920 Hom.: 0 Cov.: 33 AF XY: 0.000162 AC XY: 12 AN XY: 74156

African (AFR) AF: 0.000483 AC: 20 AN: 41404

American (AMR) AF: 0.00 AC: 0 AN: 15236

Ashkenazi Jewish (ASJ) AF: 0.000865 AC: 3 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5132

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

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

European-Non Finnish (NFE) AF: 0.0000442 AC: 3 AN: 67928

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.000198 Hom.: 0

Bravo AF: 0.000185

ESP6500AA AF: 0.000517 AC: 2

ESP6500EA AF: 0.000121 AC: 1

ExAC AF: 0.0000580 AC: 7

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	1	not provided (3)
-	1	1	not specified (2)
-	-	1	Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G (1)
-	-	1	Cardiovascular phenotype (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	20
DANN	Benign	0.94
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.092
FATHMM_MKL	Benign	0.15	N
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.063	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.96	L
PhyloP100		2.9
PrimateAI	Benign	0.37	T
PROVEAN	Uncertain	-2.7	D
REVEL	Benign	0.13
Sift	Benign	0.12	T
Polyphen		0.0060	B
Vest4		0.30
MVP		0.29
MPC		0.10
ClinPred		0.015	T
GERP RS		4.8
Mutation Taster		=92/8	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: rs367603302; hg19: chr2-179474033; COSMIC: COSV60215483; COSMIC: COSV60215483;