2-178752043-GAAAAA-GAA

Variant names:

• chr2-178752043-GAAA-G
• rs58651353
• NM_001267550.2:c.11311+1078_11311+1080delTTT

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP6

The NM_133379.5(TTN):​c.10361-7_10361-5delTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000805 in 1,396,478 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 0)
  • Exomes 𝑓: 0.00088 (0 hom.)
• Consequence: TTN NM_133379.5 splice_region, intron
• Clinical Significance: Benign no assertion criteria provided B:3
• Conservation: PhyloP100: 3.55
• Publications: 5 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: Likely_benign. The variant received -1 ACMG points.

• BP6: Variant 2-178752043-GAAA-G is Benign according to our data. Variant chr2-178752043-GAAA-G is described in ClinVar as Benign. ClinVar VariationId is 1174725.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_133379.5. 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.11311+1078_11311+1080delTTT		intron	N/A	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.10360+1078_10360+1080delTTT		intron	N/A	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.10360+1078_10360+1080delTTT		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.11311+1078_11311+1080delTTT		intron	N/A	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.11311+1078_11311+1080delTTT		intron	N/A	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.11035+1078_11035+1080delTTT		intron	N/A	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.000156 AC: 22 AN: 140934 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.0000783

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00111

Gnomad FIN AF: 0.000240

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000186

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00164 AC: 267 AN: 162534 AF XY: 0.00165

Gnomad AFR exome AF: 0.000803

Gnomad AMR exome AF: 0.000903

Gnomad ASJ exome AF: 0.00223

Gnomad EAS exome AF: 0.00108

Gnomad FIN exome AF: 0.00188

Gnomad NFE exome AF: 0.00193

Gnomad OTH exome AF: 0.00264

GnomAD4 exome AF: 0.000878 AC: 1102 AN: 1255490 Hom.: 0 AF XY: 0.000894 AC XY: 562 AN XY: 628570

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

African (AFR) AF: 0.000228 AC: 6 AN: 26348

American (AMR) AF: 0.000838 AC: 27 AN: 32212

Ashkenazi Jewish (ASJ) AF: 0.00100 AC: 23 AN: 22938

East Asian (EAS) AF: 0.000317 AC: 11 AN: 34718

South Asian (SAS) AF: 0.00181 AC: 131 AN: 72280

European-Finnish (FIN) AF: 0.00108 AC: 48 AN: 44328

Middle Eastern (MID) AF: 0.00181 AC: 9 AN: 4982

European-Non Finnish (NFE) AF: 0.000846 AC: 817 AN: 965462

Other (OTH) AF: 0.000574 AC: 30 AN: 52222

⚠️ 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: 0.000156 AC: 22 AN: 140988 Hom.: 0 Cov.: 0 AF XY: 0.000132 AC XY: 9 AN XY: 68254

African (AFR) AF: 0.0000781 AC: 3 AN: 38418

American (AMR) AF: 0.00 AC: 0 AN: 14046

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3308

East Asian (EAS) AF: 0.00 AC: 0 AN: 4874

South Asian (SAS) AF: 0.00112 AC: 5 AN: 4466

European-Finnish (FIN) AF: 0.000240 AC: 2 AN: 8348

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 278

European-Non Finnish (NFE) AF: 0.000186 AC: 12 AN: 64436

Other (OTH) AF: 0.00 AC: 0 AN: 1934

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.6
Mutation Taster		=64/36	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs58651353; hg19: chr2-179616770;