2-178713381-TACAAAACAAAACAAA-TACAAAACAAAACAAAACAAAACAAA

Variant names:

• chr2-178713381-T-TACAAAACAAA
• rs71393436
• NM_001267550.2:c.26762-19_26762-10dupTTTGTTTTGT

Variant summary

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

The NM_001267550.2(TTN):​c.26762-19_26762-10dupTTTGTTTTGT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00389 in 1,468,934 control chromosomes in the GnomAD database, including 71 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (42 hom., cov: 24)
  • Exomes 𝑓: 0.0027 (29 hom.)
• Consequence: TTN NM_001267550.2 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 1.08
• 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: Benign. The variant received -16 ACMG points.

• BP6: Variant 2-178713381-T-TACAAAACAAA is Benign according to our data. Variant chr2-178713381-T-TACAAAACAAA is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 167796.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 = 0.0142 (2150/150994) while in subpopulation AFR AF = 0.0452 (1854/41010). AF 95% confidence interval is 0.0435. There are 42 homozygotes in GnomAd4. There are 971 alleles in the male GnomAd4 subpopulation. Median coverage is 24. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 42 AD,AR gene

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.26762-19_26762-10dupTTTGTTTTGT		intron	N/A	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.25811-19_25811-10dupTTTGTTTTGT		intron	N/A	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.23030-19_23030-10dupTTTGTTTTGT		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.26762-10_26762-9insTTTGTTTTGT		intron	N/A	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.26762-10_26762-9insTTTGTTTTGT		intron	N/A	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.26486-10_26486-9insTTTGTTTTGT		intron	N/A	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.0141 AC: 2129 AN: 150878 Hom.: 38 Cov.: 24

Gnomad AFR AF: 0.0448

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00700

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00276

Gnomad SAS AF: 0.00169

Gnomad FIN AF: 0.000763

Gnomad MID AF: 0.00637

Gnomad NFE AF: 0.00198

Gnomad OTH AF: 0.0116

GnomAD2 exomes AF: 0.00456 AC: 458 AN: 100440 AF XY: 0.00376

Gnomad AFR exome AF: 0.0411

Gnomad AMR exome AF: 0.00459

Gnomad ASJ exome AF: 0.000479

Gnomad EAS exome AF: 0.00231

Gnomad FIN exome AF: 0.00104

Gnomad NFE exome AF: 0.00134

Gnomad OTH exome AF: 0.00107

GnomAD4 exome AF: 0.00270 AC: 3562 AN: 1317940 Hom.: 29 Cov.: 33 AF XY: 0.00255 AC XY: 1636 AN XY: 641860

African (AFR) AF: 0.0413 AC: 1180 AN: 28580

American (AMR) AF: 0.00572 AC: 126 AN: 22036

Ashkenazi Jewish (ASJ) AF: 0.000283 AC: 6 AN: 21170

East Asian (EAS) AF: 0.00216 AC: 74 AN: 34336

South Asian (SAS) AF: 0.00128 AC: 80 AN: 62456

European-Finnish (FIN) AF: 0.00158 AC: 74 AN: 46854

Middle Eastern (MID) AF: 0.00350 AC: 14 AN: 4004

European-Non Finnish (NFE) AF: 0.00170 AC: 1776 AN: 1044210

Other (OTH) AF: 0.00427 AC: 232 AN: 54294

GnomAD4 genome AF: 0.0142 AC: 2150 AN: 150994 Hom.: 42 Cov.: 24 AF XY: 0.0132 AC XY: 971 AN XY: 73698

African (AFR) AF: 0.0452 AC: 1854 AN: 41010

American (AMR) AF: 0.00699 AC: 106 AN: 15154

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00277 AC: 14 AN: 5054

South Asian (SAS) AF: 0.00169 AC: 8 AN: 4734

European-Finnish (FIN) AF: 0.000763 AC: 8 AN: 10480

Middle Eastern (MID) AF: 0.00685 AC: 2 AN: 292

European-Non Finnish (NFE) AF: 0.00198 AC: 134 AN: 67800

Other (OTH) AF: 0.0114 AC: 24 AN: 2098

Alfa AF: 0.00152 Hom.: 211

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	1	Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G (1)
-	-	1	Cardiomyopathy (1)
-	-	1	Dilated Cardiomyopathy, Dominant (1)
-	-	1	Early-onset myopathy with fatal cardiomyopathy (1)
-	-	1	Hypertrophic cardiomyopathy (1)
-	-	1	Limb-girdle muscular dystrophy, recessive (1)
-	-	1	Myopathy, myofibrillar, 9, with early respiratory failure (1)
-	-	1	not provided (1)
-	-	1	Tibial muscular dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.1
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: rs71393436; hg19: chr2-179578108;