2-178729703-C-T

Variant names:

• chr2-178729703-C-T
• rs72648947
• NM_001267550.2:c.18550G>A

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS1

The NM_001267550.2(TTN):​c.18550G>A​(p.Ala6184Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000369 in 1,613,708 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A6184A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00045 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00036 (1 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:4
• Conservation: PhyloP100: 7.57
• Publications: 7 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 -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.17472166).
• BP6: Variant 2-178729703-C-T is Benign according to our data. Variant chr2-178729703-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 203272.
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.000361 (528/1461476) while in subpopulation MID AF = 0.00365 (21/5760). AF 95% confidence interval is 0.00244. There are 1 homozygotes in GnomAdExome4. There are 287 alleles in the male GnomAdExome4 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.18550G>A	p.Ala6184Thr	missense	Exon 63 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.17599G>A	p.Ala5867Thr	missense	Exon 61 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.14818G>A	p.Ala4940Thr	missense	Exon 60 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.18550G>A	p.Ala6184Thr	missense	Exon 63 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.18550G>A	p.Ala6184Thr	missense	Exon 63 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.18274G>A	p.Ala6092Thr	missense	Exon 61 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.000454 AC: 69 AN: 152114 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00203

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000485

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000403 AC: 100 AN: 248312 AF XY: 0.000460

Gnomad AFR exome AF: 0.000129

Gnomad AMR exome AF: 0.000638

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000928

Gnomad NFE exome AF: 0.000597

Gnomad OTH exome AF: 0.000332

GnomAD4 exome AF: 0.000361 AC: 528 AN: 1461476 Hom.: 1 Cov.: 33 AF XY: 0.000395 AC XY: 287 AN XY: 727012

African (AFR) AF: 0.000179 AC: 6 AN: 33458

American (AMR) AF: 0.000514 AC: 23 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39692

South Asian (SAS) AF: 0.000174 AC: 15 AN: 86252

European-Finnish (FIN) AF: 0.000300 AC: 16 AN: 53400

Middle Eastern (MID) AF: 0.00365 AC: 21 AN: 5760

European-Non Finnish (NFE) AF: 0.000378 AC: 420 AN: 1111712

Other (OTH) AF: 0.000431 AC: 26 AN: 60360

GnomAD4 genome AF: 0.000447 AC: 68 AN: 152232 Hom.: 1 Cov.: 33 AF XY: 0.000497 AC XY: 37 AN XY: 74408

African (AFR) AF: 0.0000481 AC: 2 AN: 41558

American (AMR) AF: 0.00203 AC: 31 AN: 15276

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.0000943 AC: 1 AN: 10610

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000485 AC: 33 AN: 67996

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000424 Hom.: 0

Bravo AF: 0.000650

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000722 AC: 6

ExAC AF: 0.000455 AC: 55

EpiCase AF: 0.000273

EpiControl AF: 0.000474

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	3	2	not provided (5)
-	1	-	Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G (1)
-	1	-	Cardiovascular phenotype (1)
-	-	1	Long QT syndrome (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	22
DANN	Benign	0.93
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.17	T
MetaSVM	Uncertain	0.40	D
PhyloP100		7.6
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-2.0	N
REVEL	Uncertain	0.42
Sift	Benign	0.34	T
Polyphen		1.0	D
Vest4		0.44
MVP		0.46
MPC		0.46
ClinPred		0.056	T
GERP RS		6.2
Mutation Taster		=44/56	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs72648947; hg19: chr2-179594430; COSMIC: COSV104645557;