2-178735748-C-T

Variant names:

• chr2-178735748-C-T
• rs72648923
• NM_001267550.2:c.14698G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001267550.2(TTN):​c.14698G>A​(p.Ala4900Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00255 in 1,613,770 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A4900V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0032 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0025 (21 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:22 O:1
• Conservation: PhyloP100: 4.96
• Publications: 19 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0078028142).
• BP6: Variant 2-178735748-C-T is Benign according to our data. Variant chr2-178735748-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 46591.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0032 (488/152300) while in subpopulation NFE AF = 0.00431 (293/68026). AF 95% confidence interval is 0.0039. There are 2 homozygotes in GnomAd4. There are 292 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 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.14698G>A	p.Ala4900Thr	missense	Exon 50 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.13747G>A	p.Ala4583Thr	missense	Exon 48 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.10966G>A	p.Ala3656Thr	missense	Exon 47 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.14698G>A	p.Ala4900Thr	missense	Exon 50 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.14698G>A	p.Ala4900Thr	missense	Exon 50 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.14422G>A	p.Ala4808Thr	missense	Exon 48 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.00321 AC: 488 AN: 152182 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.0160

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00431

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00344 AC: 855 AN: 248448 AF XY: 0.00352

Gnomad AFR exome AF: 0.000129

Gnomad AMR exome AF: 0.000435

Gnomad ASJ exome AF: 0.00189

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0156

Gnomad NFE exome AF: 0.00401

Gnomad OTH exome AF: 0.00249

GnomAD4 exome AF: 0.00248 AC: 3623 AN: 1461470 Hom.: 21 Cov.: 29 AF XY: 0.00261 AC XY: 1896 AN XY: 727002

African (AFR) AF: 0.0000597 AC: 2 AN: 33474

American (AMR) AF: 0.000514 AC: 23 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 30 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39638

South Asian (SAS) AF: 0.000649 AC: 56 AN: 86254

European-Finnish (FIN) AF: 0.0155 AC: 826 AN: 53368

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5766

European-Non Finnish (NFE) AF: 0.00230 AC: 2561 AN: 1111770

Other (OTH) AF: 0.00204 AC: 123 AN: 60360

GnomAD4 genome AF: 0.00320 AC: 488 AN: 152300 Hom.: 2 Cov.: 33 AF XY: 0.00392 AC XY: 292 AN XY: 74472

African (AFR) AF: 0.0000962 AC: 4 AN: 41578

American (AMR) AF: 0.000196 AC: 3 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00202 AC: 7 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4830

European-Finnish (FIN) AF: 0.0160 AC: 170 AN: 10610

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

European-Non Finnish (NFE) AF: 0.00431 AC: 293 AN: 68026

Other (OTH) AF: 0.00189 AC: 4 AN: 2114

Alfa AF: 0.00363 Hom.: 6

Bravo AF: 0.00150

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.000267 AC: 1

ESP6500EA AF: 0.00328 AC: 27

ExAC AF: 0.00341 AC: 412

Asia WGS AF: 0.000578 AC: 2 AN: 3476

EpiCase AF: 0.00284

EpiControl AF: 0.00219

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not provided (7)
-	-	6	not specified (6)
-	-	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	Long QT syndrome (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	0.11
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	22
DANN	Benign	0.91
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.79	T
MetaRNN	Benign	0.0078	T
MetaSVM	Benign	-0.37	T
PhyloP100		5.0
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-1.7	N
REVEL	Uncertain	0.29
Sift	Benign	0.74	T
Polyphen		1.0	D
Vest4		0.30
MVP		0.55
MPC		0.44
ClinPred		0.052	T
GERP RS		5.8
Mutation Taster		=56/44	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: rs72648923; hg19: chr2-179600475; COSMIC: COSV104640826; COSMIC: COSV104640826;