2-178750225-A-G

Variant names:

• chr2-178750225-A-G
• rs10803917
• NM_001267550.2:c.11311+2899T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001267550.2(TTN):​c.11311+2899T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.996 in 1,613,152 control chromosomes in the GnomAD database, including 799,682 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.98 (72533 hom., cov: 30)
  • Exomes 𝑓: 1.0 (727149 hom.)
• Consequence: TTN NM_001267550.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.0310
• Publications: 18 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 (BayesDel_noAF=-0.87).
• BP6: Variant 2-178750225-A-G is Benign according to our data. Variant chr2-178750225-A-G is described in ClinVar as Benign. ClinVar VariationId is 47743.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.993 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	NM_001267550.2	MANE Select	c.11311+2899T>C		intron	N/A	NP_001254479.2
	TTN	NM_133379.5		c.12175T>C	p.Leu4059Leu	synonymous	Exon 46 of 46	NP_596870.2
	TTN	NM_001256850.1		c.10360+2899T>C		intron	N/A	NP_001243779.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	ENST00000589042.5	TSL:5 MANE Select	c.11311+2899T>C		intron	N/A	ENSP00000467141.1
	TTN	ENST00000446966.2	TSL:1	c.11311+2899T>C		intron	N/A	ENSP00000408004.2
	TTN	ENST00000436599.2	TSL:1	c.11035+2899T>C		intron	N/A	ENSP00000405517.2

Frequencies

GnomAD3 genomes AF: 0.977 AC: 148267 AN: 151830 Hom.: 72506 Cov.: 30

Gnomad AFR AF: 0.918

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.994

Gnomad ASJ AF: 1.00

Gnomad EAS AF: 1.00

Gnomad SAS AF: 1.00

Gnomad FIN AF: 1.00

Gnomad MID AF: 0.994

Gnomad NFE AF: 1.00

Gnomad OTH AF: 0.981

GnomAD2 exomes AF: 0.994 AC: 249410 AN: 250868 AF XY: 0.996

Gnomad AFR exome AF: 0.920

Gnomad AMR exome AF: 0.997

Gnomad ASJ exome AF: 1.00

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 1.00

Gnomad NFE exome AF: 1.00

Gnomad OTH exome AF: 0.997

GnomAD4 exome AF: 0.998 AC: 1457614 AN: 1461204 Hom.: 727149 Cov.: 80 AF XY: 0.998 AC XY: 725397 AN XY: 726910

African (AFR) AF: 0.912 AC: 30494 AN: 33438

American (AMR) AF: 0.996 AC: 44492 AN: 44650

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 26114 AN: 26114

East Asian (EAS) AF: 1.00 AC: 39664 AN: 39664

South Asian (SAS) AF: 1.00 AC: 86209 AN: 86234

European-Finnish (FIN) AF: 1.00 AC: 53394 AN: 53394

Middle Eastern (MID) AF: 0.996 AC: 5736 AN: 5758

European-Non Finnish (NFE) AF: 1.00 AC: 1111517 AN: 1111596

Other (OTH) AF: 0.994 AC: 59994 AN: 60356

GnomAD4 genome AF: 0.976 AC: 148350 AN: 151948 Hom.: 72533 Cov.: 30 AF XY: 0.977 AC XY: 72614 AN XY: 74288

African (AFR) AF: 0.917 AC: 38036 AN: 41478

American (AMR) AF: 0.994 AC: 15117 AN: 15210

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 3464 AN: 3464

East Asian (EAS) AF: 1.00 AC: 5160 AN: 5160

South Asian (SAS) AF: 1.00 AC: 4802 AN: 4804

European-Finnish (FIN) AF: 1.00 AC: 10624 AN: 10624

Middle Eastern (MID) AF: 0.993 AC: 292 AN: 294

European-Non Finnish (NFE) AF: 1.00 AC: 67879 AN: 67898

Other (OTH) AF: 0.981 AC: 2064 AN: 2104

Alfa AF: 0.988 Hom.: 49668

Bravo AF: 0.973

Asia WGS AF: 0.992 AC: 3449 AN: 3476

EpiCase AF: 1.00

EpiControl AF: 1.00

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	2.9
DANN	Benign	0.66
PhyloP100		-0.031
Mutation Taster		=100/0	polymorphism (auto)

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: rs10803917; hg19: chr2-179614952; COSMIC: COSV108173315; COSMIC: COSV108173315;