2-178752043-GAAAAA-GAAAA

Variant names:

• chr2-178752043-GA-G
• rs58651353
• NM_001267550.2:c.11311+1080delT

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.10361-5delT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.69 (33400 hom., cov: 0)
  • Exomes 𝑓: 0.45 (13505 hom.)
  • Failed GnomAD Quality Control
• Consequence: TTN NM_133379.5 splice_region, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:2 B:7
• Conservation: PhyloP100: 2.56
• 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-GA-G is Benign according to our data. Variant chr2-178752043-GA-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 47724.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.89 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+1080delT		intron	N/A	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.10360+1080delT		intron	N/A	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.10360+1080delT		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+1080delT		intron	N/A	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.11311+1080delT		intron	N/A	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.11035+1080delT		intron	N/A	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.692 AC: 97487 AN: 140786 Hom.: 33390 Cov.: 0

Gnomad AFR AF: 0.762

Gnomad AMI AF: 0.808

Gnomad AMR AF: 0.645

Gnomad ASJ AF: 0.555

Gnomad EAS AF: 0.913

Gnomad SAS AF: 0.647

Gnomad FIN AF: 0.706

Gnomad MID AF: 0.582

Gnomad NFE AF: 0.653

Gnomad OTH AF: 0.658

GnomAD2 exomes AF: 0.463 AC: 75306 AN: 162534 AF XY: 0.461

Gnomad AFR exome AF: 0.482

Gnomad AMR exome AF: 0.460

Gnomad ASJ exome AF: 0.417

Gnomad EAS exome AF: 0.502

Gnomad FIN exome AF: 0.494

Gnomad NFE exome AF: 0.458

Gnomad OTH exome AF: 0.454

GnomAD4 exome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.454 AC: 564297 AN: 1243988 Hom.: 13505 Cov.: 0 AF XY: 0.453 AC XY: 281815 AN XY: 622722

African (AFR) AF: 0.484 AC: 12714 AN: 26250

American (AMR) AF: 0.447 AC: 14224 AN: 31856

Ashkenazi Jewish (ASJ) AF: 0.404 AC: 9112 AN: 22566

East Asian (EAS) AF: 0.506 AC: 17564 AN: 34720

South Asian (SAS) AF: 0.439 AC: 31424 AN: 71536

European-Finnish (FIN) AF: 0.470 AC: 20666 AN: 44008

Middle Eastern (MID) AF: 0.472 AC: 2311 AN: 4896

European-Non Finnish (NFE) AF: 0.453 AC: 432831 AN: 956430

Other (OTH) AF: 0.453 AC: 23451 AN: 51726

GnomAD4 genome AF: 0.692 AC: 97520 AN: 140838 Hom.: 33400 Cov.: 0 AF XY: 0.693 AC XY: 47224 AN XY: 68180

African (AFR) AF: 0.762 AC: 29246 AN: 38372

American (AMR) AF: 0.645 AC: 9055 AN: 14036

Ashkenazi Jewish (ASJ) AF: 0.555 AC: 1836 AN: 3306

East Asian (EAS) AF: 0.913 AC: 4441 AN: 4866

South Asian (SAS) AF: 0.646 AC: 2876 AN: 4454

European-Finnish (FIN) AF: 0.706 AC: 5886 AN: 8338

Middle Eastern (MID) AF: 0.597 AC: 166 AN: 278

European-Non Finnish (NFE) AF: 0.653 AC: 42026 AN: 64376

Other (OTH) AF: 0.661 AC: 1277 AN: 1932

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	2	not provided (2)
-	1	-	Dilated cardiomyopathy 1G (1)
-	1	-	Hypertrophic cardiomyopathy 9 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.6
Mutation Taster		=90/10	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs58651353;

hg19: chr2-179616770;

COSMIC: COSV60224085;

COSMIC: COSV60224085;