rs371496970

Variant names:

• chr2-178719315-A-C
• rs371496970
• NM_001267550.2:c.24075T>G

Your query was ambiguous. Multiple possible variants found:

• chr2-178719315-A-C
• chr2-178719315-A-G

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The NM_001267550.2(TTN):​c.24075T>G​(p.Ile8025Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000599 in 1,613,674 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 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. I8025I) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00035 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00062 (9 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:10
• Conservation: PhyloP100: -2.01
• 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.

• BP6: Variant 2-178719315-A-C is Benign according to our data. Variant chr2-178719315-A-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 179055.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000348 (53/152114) while in subpopulation SAS AF = 0.0104 (50/4824). AF 95% confidence interval is 0.00808. There are 1 homozygotes in GnomAd4. There are 39 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 9 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.24075T>G	p.Ile8025Met	missense	Exon 83 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.23124T>G	p.Ile7708Met	missense	Exon 81 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.20343T>G	p.Ile6781Met	missense	Exon 80 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.24075T>G	p.Ile8025Met	missense	Exon 83 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.24075T>G	p.Ile8025Met	missense	Exon 83 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.23799T>G	p.Ile7933Met	missense	Exon 81 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.000362 AC: 55 AN: 151996 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0108

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.00116 AC: 288 AN: 248868 AF XY: 0.00170

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000178

Gnomad OTH exome AF: 0.000497

GnomAD4 exome AF: 0.000625 AC: 913 AN: 1461560 Hom.: 9 Cov.: 35 AF XY: 0.000920 AC XY: 669 AN XY: 727060

African (AFR) AF: 0.00 AC: 0 AN: 33466

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.0101 AC: 867 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

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

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111758

Other (OTH) AF: 0.000663 AC: 40 AN: 60362

GnomAD4 genome AF: 0.000348 AC: 53 AN: 152114 Hom.: 1 Cov.: 32 AF XY: 0.000524 AC XY: 39 AN XY: 74374

African (AFR) AF: 0.00 AC: 0 AN: 41526

American (AMR) AF: 0.0000655 AC: 1 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5154

South Asian (SAS) AF: 0.0104 AC: 50 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67960

Other (OTH) AF: 0.000474 AC: 1 AN: 2108

Alfa AF: 0.0000310 Hom.: 0

Bravo AF: 0.0000793

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000121 AC: 1

ExAC AF: 0.00122 AC: 147

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	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	Dilated cardiomyopathy 1G (1)
-	-	1	Early-onset myopathy with fatal cardiomyopathy (1)
-	-	1	Myopathy, myofibrillar, 9, with early respiratory failure (1)
-	-	1	not provided (1)
-	-	1	Tibial muscular dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	7.4
DANN	Benign	0.85
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.71
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.73	T
MetaRNN	Benign	0.0068	T
MetaSVM	Benign	-0.45	T
PhyloP100		-2.0
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-1.9	N
REVEL	Uncertain	0.30
Sift	Benign	0.12	T
Polyphen		0.50	P
Vest4		0.32
MVP		0.32
MPC		0.20
ClinPred		0.057	T
GERP RS		-4.8
Mutation Taster		=92/8	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.29		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.29		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs371496970; hg19: chr2-179584042;