chr2-178728975-C-A

Variant names:

• chr2-178728975-C-A
• rs188878341
• NM_001267550.2:c.19063G>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_001267550.2(TTN):​c.19063G>T​(p.Asp6355Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000133 in 1,613,092 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D6355G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00063 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000081 (0 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:4
• Conservation: PhyloP100: 7.57
• 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: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.026508152).
• BP6: Variant 2-178728975-C-A is Benign according to our data. Variant chr2-178728975-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 178247.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000631 (96/152230) while in subpopulation AFR AF = 0.00207 (86/41550). AF 95% confidence interval is 0.00172. There are 0 homozygotes in GnomAd4. There are 57 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

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.19063G>T	p.Asp6355Tyr	missense	Exon 65 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.18112G>T	p.Asp6038Tyr	missense	Exon 63 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.15331G>T	p.Asp5111Tyr	missense	Exon 62 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.19063G>T	p.Asp6355Tyr	missense	Exon 65 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.19063G>T	p.Asp6355Tyr	missense	Exon 65 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.18787G>T	p.Asp6263Tyr	missense	Exon 63 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.000631 AC: 96 AN: 152112 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00208

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000190 AC: 47 AN: 247214 AF XY: 0.000112

Gnomad AFR exome AF: 0.00259

Gnomad AMR exome AF: 0.000175

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000167

GnomAD4 exome AF: 0.0000815 AC: 119 AN: 1460862 Hom.: 0 Cov.: 33 AF XY: 0.0000661 AC XY: 48 AN XY: 726692

African (AFR) AF: 0.00314 AC: 105 AN: 33442

American (AMR) AF: 0.000157 AC: 7 AN: 44630

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26106

East Asian (EAS) AF: 0.00 AC: 0 AN: 39610

South Asian (SAS) AF: 0.00 AC: 0 AN: 86198

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53258

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111546

Other (OTH) AF: 0.000116 AC: 7 AN: 60316

GnomAD4 genome AF: 0.000631 AC: 96 AN: 152230 Hom.: 0 Cov.: 33 AF XY: 0.000766 AC XY: 57 AN XY: 74424

African (AFR) AF: 0.00207 AC: 86 AN: 41550

American (AMR) AF: 0.000588 AC: 9 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5162

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67992

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.000222 Hom.: 0

Bravo AF: 0.000982

ESP6500AA AF: 0.00237 AC: 9

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000199 AC: 24

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.15
CADD	Uncertain	23
DANN	Benign	0.80
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.73	T
M_CAP	Benign	0.044	D
MetaRNN	Benign	0.027	T
MetaSVM	Benign	-0.30	T
PhyloP100		7.6
PrimateAI	Uncertain	0.53	T
PROVEAN	Pathogenic	-5.2	D
REVEL	Uncertain	0.43
Sift	Benign	0.031	D
Polyphen		0.99	D
Vest4		0.39
MVP		0.69
MPC		0.46
ClinPred		0.047	T
GERP RS		5.9
Mutation Taster		=14/86	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs188878341; hg19: chr2-179593702;