rs186497293

Variant names:

• chr2-178615650-T-C
• rs186497293
• NM_001267550.2:c.48451A>G

Your query was ambiguous. Multiple possible variants found:

• chr2-178615650-T-C
• chr2-178615650-T-G

Variant summary

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

The ENST00000589042.5(TTN):​c.48451A>G​(p.Thr16151Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000133 in 1,612,246 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/20 in silico tools predict 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. T16151P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00068 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000076 (0 hom.)
• Consequence: TTN ENST00000589042.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:9
• Conservation: PhyloP100: 3.17
• Publications: 0 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=0.0052808225).
• BP6: Variant 2-178615650-T-C is Benign according to our data. Variant chr2-178615650-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 264279.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000678 (103/151934) while in subpopulation AFR AF = 0.00229 (95/41500). AF 95% confidence interval is 0.00192. There are 0 homozygotes in GnomAd4. There are 53 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000589042.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	NM_001267550.2	MANE Select	c.48451A>G	p.Thr16151Ala	missense	Exon 258 of 363	NP_001254479.2
	TTN	NM_001256850.1		c.43528A>G	p.Thr14510Ala	missense	Exon 208 of 313	NP_001243779.1
	TTN	NM_133378.4		c.40747A>G	p.Thr13583Ala	missense	Exon 207 of 312	NP_596869.4

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	ENST00000589042.5	TSL:5 MANE Select	c.48451A>G	p.Thr16151Ala	missense	Exon 258 of 363	ENSP00000467141.1
	TTN	ENST00000446966.2	TSL:1	c.48295A>G	p.Thr16099Ala	missense	Exon 256 of 361	ENSP00000408004.2
	TTN	ENST00000436599.2	TSL:1	c.48175A>G	p.Thr16059Ala	missense	Exon 256 of 361	ENSP00000405517.2

Frequencies

GnomAD3 genomes AF: 0.000672 AC: 102 AN: 151816 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00227

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000394

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000196

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000185 AC: 46 AN: 248082 AF XY: 0.000111

Gnomad AFR exome AF: 0.00227

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000112

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000178

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.0000760 AC: 111 AN: 1460312 Hom.: 0 Cov.: 32 AF XY: 0.0000633 AC XY: 46 AN XY: 726450

African (AFR) AF: 0.00240 AC: 80 AN: 33374

American (AMR) AF: 0.000202 AC: 9 AN: 44662

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26076

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39660

South Asian (SAS) AF: 0.00 AC: 0 AN: 86096

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53400

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5750

European-Non Finnish (NFE) AF: 0.00000810 AC: 9 AN: 1111012

Other (OTH) AF: 0.000182 AC: 11 AN: 60282

GnomAD4 genome AF: 0.000678 AC: 103 AN: 151934 Hom.: 0 Cov.: 32 AF XY: 0.000714 AC XY: 53 AN XY: 74232

African (AFR) AF: 0.00229 AC: 95 AN: 41500

American (AMR) AF: 0.000394 AC: 6 AN: 15244

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

East Asian (EAS) AF: 0.000196 AC: 1 AN: 5102

South Asian (SAS) AF: 0.00 AC: 0 AN: 4808

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67896

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000284 Hom.: 0

Bravo AF: 0.000771

ESP6500AA AF: 0.00262 AC: 10

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000281 AC: 34

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	3	not provided (4)
-	-	2	not specified (2)
-	-	1	Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Limb-girdle muscular dystrophy (1)
-	-	1	TTN-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.052
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	18
DANN	Benign	0.79
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.093
FATHMM_MKL	Benign	0.50	D
LIST_S2	Benign	0.50	T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.0053	T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	-0.39	N
PhyloP100		3.2
PrimateAI	Benign	0.33	T
PROVEAN	Benign	1.1	N
REVEL	Benign	0.16
Sift	Benign	0.87	T
Polyphen		0.0	B
Vest4		0.024
MVP		0.28
MPC		0.082
ClinPred		0.0052	T
GERP RS		4.0
Mutation Taster		=85/15	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: rs186497293; hg19: chr2-179480377;