2-178702075-TAA-TA

Variant names:

• chr2-178702075-TA-T
• rs397517532
• NM_001267550.2:c.30512-10delT

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP6_Moderate

The NM_001267550.2(TTN):​c.30512-10delT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000714 in 1,465,442 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.00010 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00078 (0 hom.)
• Consequence: TTN NM_001267550.2 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.83
• Publications: 1 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]

LOC124906100 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP6: Variant 2-178702075-TA-T is Benign according to our data. Variant chr2-178702075-TA-T is described in ClinVar as Benign. ClinVar VariationId is 1954937.Status of the report is criteria_provided_single_submitter, 1 stars.

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.30512-10delT		intron	N/A	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.29561-10delT		intron	N/A	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.26780-10delT		intron	N/A	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.30512-10delT		intron	N/A	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.30512-10delT		intron	N/A	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.30236-10delT		intron	N/A	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.000100 AC: 15 AN: 149824 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000122

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000990

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000134

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00270 AC: 464 AN: 172130 AF XY: 0.00284

Gnomad AFR exome AF: 0.00110

Gnomad AMR exome AF: 0.00235

Gnomad ASJ exome AF: 0.00343

Gnomad EAS exome AF: 0.00276

Gnomad FIN exome AF: 0.000850

Gnomad NFE exome AF: 0.00331

Gnomad OTH exome AF: 0.00270

GnomAD4 exome AF: 0.000784 AC: 1031 AN: 1315618 Hom.: 0 Cov.: 32 AF XY: 0.000842 AC XY: 550 AN XY: 653192

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000918 AC: 28 AN: 30498

American (AMR) AF: 0.00170 AC: 68 AN: 40024

Ashkenazi Jewish (ASJ) AF: 0.000870 AC: 20 AN: 22984

East Asian (EAS) AF: 0.000363 AC: 13 AN: 35782

South Asian (SAS) AF: 0.00135 AC: 104 AN: 76842

European-Finnish (FIN) AF: 0.000372 AC: 18 AN: 48422

Middle Eastern (MID) AF: 0.000566 AC: 3 AN: 5304

European-Non Finnish (NFE) AF: 0.000743 AC: 744 AN: 1001360

Other (OTH) AF: 0.000607 AC: 33 AN: 54402

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000100 AC: 15 AN: 149824 Hom.: 0 Cov.: 31 AF XY: 0.000123 AC XY: 9 AN XY: 73094

African (AFR) AF: 0.000122 AC: 5 AN: 40826

American (AMR) AF: 0.00 AC: 0 AN: 15062

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3446

East Asian (EAS) AF: 0.00 AC: 0 AN: 5132

South Asian (SAS) AF: 0.00 AC: 0 AN: 4734

European-Finnish (FIN) AF: 0.0000990 AC: 1 AN: 10098

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.000134 AC: 9 AN: 67264

Other (OTH) AF: 0.00 AC: 0 AN: 2038

Alfa AF: 0.0114 Hom.: 12

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.8
Mutation Taster		=100/0	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: rs397517532; hg19: chr2-179566802; COSMIC: COSV60280191;