rs144668626

Variant names:

• chr2-178621649-C-T
• rs144668626
• NM_001267550.2:c.45175G>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.45175G>A​(p.Ala15059Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00187 in 1,612,382 control chromosomes in the GnomAD database, including 34 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A15059A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0016 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0019 (30 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:28
• Conservation: PhyloP100: 7.86
• Publications: 11 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=0.006442368).
• BP6: Variant 2-178621649-C-T is Benign according to our data. Variant chr2-178621649-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 46982.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0016 (243/151912) while in subpopulation SAS AF = 0.0193 (93/4820). AF 95% confidence interval is 0.0161. There are 4 homozygotes in GnomAd4. There are 132 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 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.45175G>A	p.Ala15059Thr	missense	Exon 245 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.40252G>A	p.Ala13418Thr	missense	Exon 195 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.37471G>A	p.Ala12491Thr	missense	Exon 194 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.45175G>A	p.Ala15059Thr	missense	Exon 245 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.45019G>A	p.Ala15007Thr	missense	Exon 243 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.44899G>A	p.Ala14967Thr	missense	Exon 243 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.00159 AC: 241 AN: 151794 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00171

Gnomad ASJ AF: 0.000866

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0189

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00165

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.00291 AC: 718 AN: 246998 AF XY: 0.00371

Gnomad AFR exome AF: 0.000194

Gnomad AMR exome AF: 0.000786

Gnomad ASJ exome AF: 0.000900

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00179

Gnomad OTH exome AF: 0.00267

GnomAD4 exome AF: 0.00189 AC: 2765 AN: 1460470 Hom.: 30 Cov.: 32 AF XY: 0.00236 AC XY: 1711 AN XY: 726526

African (AFR) AF: 0.000269 AC: 9 AN: 33400

American (AMR) AF: 0.000695 AC: 31 AN: 44618

Ashkenazi Jewish (ASJ) AF: 0.000881 AC: 23 AN: 26094

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39540

South Asian (SAS) AF: 0.0155 AC: 1333 AN: 86226

European-Finnish (FIN) AF: 0.0000750 AC: 4 AN: 53346

Middle Eastern (MID) AF: 0.00348 AC: 20 AN: 5754

European-Non Finnish (NFE) AF: 0.00108 AC: 1201 AN: 1111202

Other (OTH) AF: 0.00237 AC: 143 AN: 60290

GnomAD4 genome AF: 0.00160 AC: 243 AN: 151912 Hom.: 4 Cov.: 32 AF XY: 0.00178 AC XY: 132 AN XY: 74214

African (AFR) AF: 0.000145 AC: 6 AN: 41496

American (AMR) AF: 0.00171 AC: 26 AN: 15242

Ashkenazi Jewish (ASJ) AF: 0.000866 AC: 3 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5114

South Asian (SAS) AF: 0.0193 AC: 93 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10588

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

European-Non Finnish (NFE) AF: 0.00165 AC: 112 AN: 67872

Other (OTH) AF: 0.00142 AC: 3 AN: 2110

Alfa AF: 0.00124 Hom.: 2

Bravo AF: 0.00104

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.000532 AC: 2

ESP6500EA AF: 0.00194 AC: 16

ExAC AF: 0.00330 AC: 398

Asia WGS AF: 0.00780 AC: 27 AN: 3476

EpiCase AF: 0.00284

EpiControl AF: 0.00273

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	10	not specified (10)
-	-	5	not provided (5)
-	-	2	Autosomal recessive limb-girdle muscular dystrophy type 2J (2)
-	-	2	Early-onset myopathy with fatal cardiomyopathy (2)
-	-	2	Myopathy, myofibrillar, 9, with early respiratory failure (2)
-	-	2	Tibial muscular dystrophy (2)
-	-	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	Primary dilated cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.18
CADD	Uncertain	23
DANN	Benign	0.97
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D
MetaRNN	Benign	0.0064	T
MetaSVM	Uncertain	-0.074	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		7.9
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-2.8	D
REVEL	Uncertain	0.37
Sift	Uncertain	0.023	D
Polyphen		1.0	D
Vest4		0.36
MVP		0.43
MPC		0.46
ClinPred		0.042	T
GERP RS		6.2
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: rs144668626; hg19: chr2-179486376; COSMIC: COSV60300967; COSMIC: COSV60300967;