2-178752043-GAAAAA-GAAA

Variant names:

• chr2-178752043-GAA-G
• rs58651353
• NM_001267550.2:c.11311+1079_11311+1080delTT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_133379.5(TTN):​c.10361-6_10361-5delTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.13 in 1,358,708 control chromosomes in the GnomAD database, including 2,092 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.086 (580 hom., cov: 0)
  • Exomes 𝑓: 0.13 (1512 hom.)
• Consequence: TTN NM_133379.5 splice_region, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 3.35
• 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: Benign. The variant received -16 ACMG points.

• BP6: Variant 2-178752043-GAA-G is Benign according to our data. Variant chr2-178752043-GAA-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 47725.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.117 is higher than 0.05.

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+1079_11311+1080delTT		intron	N/A	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.10360+1079_10360+1080delTT		intron	N/A	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.10360+1079_10360+1080delTT		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+1079_11311+1080delTT		intron	N/A	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.11311+1079_11311+1080delTT		intron	N/A	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.11035+1079_11035+1080delTT		intron	N/A	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.0856 AC: 12065 AN: 140878 Hom.: 581 Cov.: 0

Gnomad AFR AF: 0.0264

Gnomad AMI AF: 0.110

Gnomad AMR AF: 0.0700

Gnomad ASJ AF: 0.107

Gnomad EAS AF: 0.0589

Gnomad SAS AF: 0.112

Gnomad FIN AF: 0.113

Gnomad MID AF: 0.132

Gnomad NFE AF: 0.119

Gnomad OTH AF: 0.0969

GnomAD2 exomes AF: 0.147 AC: 23813 AN: 162534 AF XY: 0.149

Gnomad AFR exome AF: 0.0945

Gnomad AMR exome AF: 0.0878

Gnomad ASJ exome AF: 0.136

Gnomad EAS exome AF: 0.161

Gnomad FIN exome AF: 0.161

Gnomad NFE exome AF: 0.167

Gnomad OTH exome AF: 0.142

GnomAD4 exome AF: 0.135 AC: 163889 AN: 1217776 Hom.: 1512 AF XY: 0.134 AC XY: 81808 AN XY: 609084

African (AFR) AF: 0.0529 AC: 1334 AN: 25194

American (AMR) AF: 0.0810 AC: 2460 AN: 30384

Ashkenazi Jewish (ASJ) AF: 0.126 AC: 2837 AN: 22486

East Asian (EAS) AF: 0.102 AC: 3211 AN: 31480

South Asian (SAS) AF: 0.128 AC: 9029 AN: 70640

European-Finnish (FIN) AF: 0.135 AC: 5655 AN: 41990

Middle Eastern (MID) AF: 0.142 AC: 686 AN: 4842

European-Non Finnish (NFE) AF: 0.140 AC: 132062 AN: 940132

Other (OTH) AF: 0.131 AC: 6615 AN: 50628

GnomAD4 genome AF: 0.0856 AC: 12068 AN: 140932 Hom.: 580 Cov.: 0 AF XY: 0.0860 AC XY: 5868 AN XY: 68224

African (AFR) AF: 0.0263 AC: 1010 AN: 38410

American (AMR) AF: 0.0699 AC: 982 AN: 14044

Ashkenazi Jewish (ASJ) AF: 0.107 AC: 354 AN: 3308

East Asian (EAS) AF: 0.0593 AC: 289 AN: 4872

South Asian (SAS) AF: 0.114 AC: 508 AN: 4464

European-Finnish (FIN) AF: 0.113 AC: 938 AN: 8328

Middle Eastern (MID) AF: 0.129 AC: 36 AN: 278

European-Non Finnish (NFE) AF: 0.119 AC: 7668 AN: 64418

Other (OTH) AF: 0.0964 AC: 186 AN: 1930

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.3
Mutation Taster		=95/5	polymorphism (auto)

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; COSMIC: COSV105913858; COSMIC: COSV105913858;