2-178725406-C-G

Variant names:

• chr2-178725406-C-G
• rs200118743
• NM_001267550.2:c.20798G>C

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_001267550.2(TTN):​c.20798G>C​(p.Gly6933Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00124 in 1,603,112 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/19 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 0.00060 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0013 (3 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:12
• Conservation: PhyloP100: 5.54
• Publications: 8 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]

ENSG00000267784 (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: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011016518).
• BP6: Variant 2-178725406-C-G is Benign according to our data. Variant chr2-178725406-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 46675.
• BS2: High Homozygotes in GnomAdExome4 at 3 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.20798G>C	p.Gly6933Ala	missense	Exon 71 of 363	NP_001254479.2
	TTN	NM_001256850.1		c.19847G>C	p.Gly6616Ala	missense	Exon 69 of 313	NP_001243779.1
	TTN	NM_133378.4		c.17066G>C	p.Gly5689Ala	missense	Exon 68 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.20798G>C	p.Gly6933Ala	missense	Exon 71 of 363	ENSP00000467141.1
	TTN	ENST00000446966.2	TSL:1	c.20798G>C	p.Gly6933Ala	missense	Exon 71 of 361	ENSP00000408004.2
	TTN	ENST00000436599.2	TSL:1	c.20522G>C	p.Gly6841Ala	missense	Exon 69 of 361	ENSP00000405517.2

Frequencies

GnomAD3 genomes AF: 0.000604 AC: 92 AN: 152204 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000752

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00109

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000630 AC: 150 AN: 238114 AF XY: 0.000668

Gnomad AFR exome AF: 0.000198

Gnomad AMR exome AF: 0.000327

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000869

Gnomad NFE exome AF: 0.00108

Gnomad OTH exome AF: 0.000348

GnomAD4 exome AF: 0.00130 AC: 1888 AN: 1450790 Hom.: 3 Cov.: 30 AF XY: 0.00121 AC XY: 873 AN XY: 720418

African (AFR) AF: 0.000150 AC: 5 AN: 33320

American (AMR) AF: 0.000522 AC: 23 AN: 44038

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25542

East Asian (EAS) AF: 0.00 AC: 0 AN: 39430

South Asian (SAS) AF: 0.00 AC: 0 AN: 84136

European-Finnish (FIN) AF: 0.000777 AC: 41 AN: 52800

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5728

European-Non Finnish (NFE) AF: 0.00160 AC: 1764 AN: 1105850

Other (OTH) AF: 0.000917 AC: 55 AN: 59946

GnomAD4 genome AF: 0.000604 AC: 92 AN: 152322 Hom.: 0 Cov.: 33 AF XY: 0.000631 AC XY: 47 AN XY: 74474

African (AFR) AF: 0.000144 AC: 6 AN: 41582

American (AMR) AF: 0.000196 AC: 3 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

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

European-Finnish (FIN) AF: 0.000752 AC: 8 AN: 10632

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

European-Non Finnish (NFE) AF: 0.00109 AC: 74 AN: 68012

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.000957 Hom.: 1

Bravo AF: 0.000756

TwinsUK AF: 0.00243 AC: 9

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000843 AC: 7

ExAC AF: 0.000571 AC: 69

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	3	3	not provided (6)
-	-	3	not specified (3)
-	1	-	Autosomal recessive limb-girdle muscular dystrophy type 2J (1)
-	-	1	Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G (1)
-	-	1	Cardiomyopathy (1)
-	-	1	Cardiovascular phenotype (1)
-	1	-	Dilated cardiomyopathy 1G (1)
-	1	-	Early-onset myopathy with fatal cardiomyopathy (1)
-	-	1	Myopathy, myofibrillar, 9, with early respiratory failure (1)
-	-	1	Tibial muscular dystrophy (1)
-	-	1	TTN-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	21
DANN	Benign	0.96
Eigen	Benign	-0.30
Eigen_PC	Benign	0.050
FATHMM_MKL	Benign	0.64	D
LIST_S2	Benign	0.75	T
M_CAP	Benign	0.0054	T
MetaRNN	Benign	0.011	T
MetaSVM	Benign	-0.93	T
PhyloP100		5.5
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.22
Sift	Benign	1.0	T
Polyphen		0.0010	B
Vest4		0.36
MVP		0.14
MPC		0.091
ClinPred		0.034	T
GERP RS		4.9
Mutation Taster		=88/12	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: rs200118743; hg19: chr2-179590133; COSMIC: COSV60158608;