rs200972189

Variant names:

• chr2-178717787-C-A
• rs200972189
• NM_001267550.2:c.25087G>T

Your query was ambiguous. Multiple possible variants found:

• chr2-178717787-C-A
• chr2-178717787-C-G
• chr2-178717787-C-T

Variant summary

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

The NM_001267550.2(TTN):​c.25087G>T​(p.Ala8363Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000142 in 1,607,364 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/19 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. A8363P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00079 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000074 (0 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:7
• Conservation: PhyloP100: -0.310
• 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=0.0064499676).
• BP6: Variant 2-178717787-C-A is Benign according to our data. Variant chr2-178717787-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 46752.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000788 (120/152202) while in subpopulation AFR AF = 0.00258 (107/41540). AF 95% confidence interval is 0.00218. There are 0 homozygotes in GnomAd4. There are 55 alleles in the male GnomAd4 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.25087G>T	p.Ala8363Ser	missense	Exon 87 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.24136G>T	p.Ala8046Ser	missense	Exon 85 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.21355G>T	p.Ala7119Ser	missense	Exon 84 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.25087G>T	p.Ala8363Ser	missense	Exon 87 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.25087G>T	p.Ala8363Ser	missense	Exon 87 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.24811G>T	p.Ala8271Ser	missense	Exon 85 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.000789 AC: 120 AN: 152084 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00258

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000957

GnomAD2 exomes AF: 0.000206 AC: 50 AN: 242328 AF XY: 0.000144

Gnomad AFR exome AF: 0.00257

Gnomad AMR exome AF: 0.000326

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000742 AC: 108 AN: 1455162 Hom.: 0 Cov.: 34 AF XY: 0.0000608 AC XY: 44 AN XY: 723166

African (AFR) AF: 0.00230 AC: 76 AN: 33058

American (AMR) AF: 0.000318 AC: 14 AN: 43968

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25894

East Asian (EAS) AF: 0.00 AC: 0 AN: 39608

South Asian (SAS) AF: 0.00 AC: 0 AN: 85218

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53062

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5706

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1108616

Other (OTH) AF: 0.000267 AC: 16 AN: 60032

GnomAD4 genome AF: 0.000788 AC: 120 AN: 152202 Hom.: 0 Cov.: 33 AF XY: 0.000739 AC XY: 55 AN XY: 74416

African (AFR) AF: 0.00258 AC: 107 AN: 41540

American (AMR) AF: 0.000654 AC: 10 AN: 15284

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

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

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67970

Other (OTH) AF: 0.000947 AC: 2 AN: 2112

Alfa AF: 0.000346 Hom.: 0

Bravo AF: 0.000892

ESP6500AA AF: 0.00298 AC: 11

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000215 AC: 26

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	4	not specified (6)
-	2	1	not provided (3)
-	-	1	Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G (1)
-	-	1	TTN-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	19
DANN	Benign	0.96
Eigen	Benign	-0.13
Eigen_PC	Benign	0.088
FATHMM_MKL	Benign	0.67	D
LIST_S2	Benign	0.69	T
M_CAP	Benign	0.0078	T
MetaRNN	Benign	0.0064	T
MetaSVM	Benign	-0.94	T
PhyloP100		-0.31
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.22
Sift	Benign	0.35	T
Polyphen		0.020	B
Vest4		0.20
MVP		0.16
MPC		0.080
ClinPred		0.020	T
GERP RS		5.9
Mutation Taster		=60/40	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs200972189; hg19: chr2-179582514;