2-178752043-GAAAAA-GAAAAAA

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_133379.5(TTN):​c.10361-5dupT 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 0.014 (33 hom., cov: 0)
  • Exomes 𝑓: 0.021 (1 hom.)
• Consequence: TTN NM_133379.5 splice_region, intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• 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-G-GA is Benign according to our data. Variant chr2-178752043-G-GA is described in ClinVar as Likely_benign. ClinVar VariationId is 1207954.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.014 (1968/140942) while in subpopulation AFR AF = 0.0409 (1572/38390). AF 95% confidence interval is 0.0393. There are 33 homozygotes in GnomAd4. There are 928 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 33 AD,AR gene

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+1080dupT		intron	N/A	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.10360+1080dupT		intron	N/A	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.10360+1080dupT		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+1080_11311+1081insT		intron	N/A	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.11311+1080_11311+1081insT		intron	N/A	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.11035+1080_11035+1081insT		intron	N/A	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.0139 AC: 1961 AN: 140890 Hom.: 32 Cov.: 0

Gnomad AFR AF: 0.0409

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00442

Gnomad ASJ AF: 0.0372

Gnomad EAS AF: 0.000205

Gnomad SAS AF: 0.00111

Gnomad FIN AF: 0.00132

Gnomad MID AF: 0.0132

Gnomad NFE AF: 0.00244

Gnomad OTH AF: 0.0172

GnomAD2 exomes AF: 0.0224 AC: 3644 AN: 162534 AF XY: 0.0213

Gnomad AFR exome AF: 0.0469

Gnomad AMR exome AF: 0.0328

Gnomad ASJ exome AF: 0.0656

Gnomad EAS exome AF: 0.00323

Gnomad FIN exome AF: 0.00919

Gnomad NFE exome AF: 0.0174

Gnomad OTH exome AF: 0.0298

GnomAD4 exome AF: 0.0214 AC: 26556 AN: 1241994 Hom.: 1 Cov.: 0 AF XY: 0.0215 AC XY: 13351 AN XY: 621590

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

African (AFR) AF: 0.0483 AC: 1258 AN: 26058

American (AMR) AF: 0.0312 AC: 988 AN: 31622

Ashkenazi Jewish (ASJ) AF: 0.0625 AC: 1397 AN: 22360

East Asian (EAS) AF: 0.00121 AC: 42 AN: 34632

South Asian (SAS) AF: 0.0271 AC: 1933 AN: 71260

European-Finnish (FIN) AF: 0.0110 AC: 486 AN: 44004

Middle Eastern (MID) AF: 0.0199 AC: 98 AN: 4924

European-Non Finnish (NFE) AF: 0.0200 AC: 19137 AN: 955574

Other (OTH) AF: 0.0236 AC: 1217 AN: 51560

⚠️ 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: 0.0140 AC: 1968 AN: 140942 Hom.: 33 Cov.: 0 AF XY: 0.0136 AC XY: 928 AN XY: 68228

African (AFR) AF: 0.0409 AC: 1572 AN: 38390

American (AMR) AF: 0.00442 AC: 62 AN: 14042

Ashkenazi Jewish (ASJ) AF: 0.0372 AC: 123 AN: 3308

East Asian (EAS) AF: 0.000205 AC: 1 AN: 4874

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

European-Finnish (FIN) AF: 0.00132 AC: 11 AN: 8344

Middle Eastern (MID) AF: 0.0144 AC: 4 AN: 278

European-Non Finnish (NFE) AF: 0.00244 AC: 157 AN: 64426

Other (OTH) AF: 0.0171 AC: 33 AN: 1934

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.6
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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;