2-178647040-GTATATATATA-GTATA

Variant names:

• chr2-178647040-GTATATA-G
• rs10580462
• NM_001267550.2:c.40222+18_40222+23delTATATA

Variant summary

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

The NM_001267550.2(TTN):​c.40222+18_40222+23delTATATA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00108 in 729,418 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000028 (0 hom., cov: 21)
  • Exomes 𝑓: 0.0013 (1 hom.)
• Consequence: TTN NM_001267550.2 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.346
• Publications: 4 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 2-178647040-GTATATA-G is Benign according to our data. Variant chr2-178647040-GTATATA-G is described in ClinVar as Likely_benign. ClinVar VariationId is 1593768.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.40222+18_40222+23delTATATA		intron	N/A	NP_001254479.2
	TTN	NM_001256850.1		c.35375-1016_35375-1011delTATATA		intron	N/A	NP_001243779.1
	TTN	NM_133378.4		c.32594-1016_32594-1011delTATATA		intron	N/A	NP_596869.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	ENST00000589042.5	TSL:5 MANE Select	c.40222+18_40222+23delTATATA		intron	N/A	ENSP00000467141.1
	TTN	ENST00000446966.2	TSL:1	c.40222+18_40222+23delTATATA		intron	N/A	ENSP00000408004.2
	TTN	ENST00000436599.2	TSL:1	c.39946+18_39946+23delTATATA		intron	N/A	ENSP00000405517.2

Frequencies

GnomAD3 genomes AF: 0.0000279 AC: 4 AN: 143278 Hom.: 0 Cov.: 21

Gnomad AFR AF: 0.0000252

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000699

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000224

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000154

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00134 AC: 787 AN: 586140 Hom.: 1 AF XY: 0.00127 AC XY: 369 AN XY: 291362

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

African (AFR) AF: 0.00502 AC: 63 AN: 12562

American (AMR) AF: 0.00402 AC: 29 AN: 7222

Ashkenazi Jewish (ASJ) AF: 0.00246 AC: 24 AN: 9760

East Asian (EAS) AF: 0.00177 AC: 34 AN: 19188

South Asian (SAS) AF: 0.00105 AC: 11 AN: 10458

European-Finnish (FIN) AF: 0.00111 AC: 31 AN: 28014

Middle Eastern (MID) AF: 0.00161 AC: 3 AN: 1860

European-Non Finnish (NFE) AF: 0.00115 AC: 543 AN: 471982

Other (OTH) AF: 0.00195 AC: 49 AN: 25094

⚠️ 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: 0.0000279 AC: 4 AN: 143278 Hom.: 0 Cov.: 21 AF XY: 0.0000288 AC XY: 2 AN XY: 69466

African (AFR) AF: 0.0000252 AC: 1 AN: 39618

American (AMR) AF: 0.0000699 AC: 1 AN: 14312

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3374

East Asian (EAS) AF: 0.00 AC: 0 AN: 4886

South Asian (SAS) AF: 0.000224 AC: 1 AN: 4464

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8656

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

European-Non Finnish (NFE) AF: 0.0000154 AC: 1 AN: 64848

Other (OTH) AF: 0.00 AC: 0 AN: 1946

Alfa AF: 0.00 Hom.: 16

ClinVar

ClinVar submissions as Germline

Significance: Likely 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		0.35
Mutation Taster		=100/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs10580462; hg19: chr2-179511767;