NM_001267550.2:c.26762-14_26762-10delTTTGT

Variant names:

• chr2-178713381-TACAAA-T
• rs71393436
• NM_001267550.2:c.26762-14_26762-10delTTTGT

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.26762-14_26762-10delTTTGT variant causes a intron change. The variant allele was found at a frequency of 0.00124 in 1,468,982 control chromosomes in the GnomAD database, including 9 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0041 (3 hom., cov: 24)
  • Exomes 𝑓: 0.00091 (6 hom.)
• Consequence: TTN NM_001267550.2 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12 O:1
• Conservation: PhyloP100: 3.61
• 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-TACAAA-T is Benign according to our data. Variant chr2-178713381-TACAAA-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 46788.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 = 0.00412 (622/151012) while in subpopulation AFR AF = 0.0128 (524/41026). AF 95% confidence interval is 0.0119. There are 3 homozygotes in GnomAd4. There are 294 alleles in the male GnomAd4 subpopulation. Median coverage is 24. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 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.26762-14_26762-10delTTTGT		intron	N/A	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.25811-14_25811-10delTTTGT		intron	N/A	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.23030-14_23030-10delTTTGT		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.26762-14_26762-10delTTTGT		intron	N/A	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.26762-14_26762-10delTTTGT		intron	N/A	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.26486-14_26486-10delTTTGT		intron	N/A	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.00406 AC: 612 AN: 150896 Hom.: 3 Cov.: 24

Gnomad AFR AF: 0.0126

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00238

Gnomad ASJ AF: 0.00663

Gnomad EAS AF: 0.000395

Gnomad SAS AF: 0.000422

Gnomad FIN AF: 0.000191

Gnomad MID AF: 0.00637

Gnomad NFE AF: 0.000339

Gnomad OTH AF: 0.00385

GnomAD2 exomes AF: 0.00152 AC: 153 AN: 100440 AF XY: 0.00131

Gnomad AFR exome AF: 0.0129

Gnomad AMR exome AF: 0.00137

Gnomad ASJ exome AF: 0.00240

Gnomad EAS exome AF: 0.000486

Gnomad FIN exome AF: 0.000148

Gnomad NFE exome AF: 0.000540

Gnomad OTH exome AF: 0.000356

GnomAD4 exome AF: 0.000914 AC: 1204 AN: 1317970 Hom.: 6 AF XY: 0.000882 AC XY: 566 AN XY: 641862

African (AFR) AF: 0.0134 AC: 382 AN: 28586

American (AMR) AF: 0.00159 AC: 35 AN: 22036

Ashkenazi Jewish (ASJ) AF: 0.00680 AC: 144 AN: 21172

East Asian (EAS) AF: 0.000233 AC: 8 AN: 34334

South Asian (SAS) AF: 0.000480 AC: 30 AN: 62450

European-Finnish (FIN) AF: 0.000384 AC: 18 AN: 46852

Middle Eastern (MID) AF: 0.00225 AC: 9 AN: 4006

European-Non Finnish (NFE) AF: 0.000433 AC: 452 AN: 1044230

Other (OTH) AF: 0.00232 AC: 126 AN: 54304

GnomAD4 genome AF: 0.00412 AC: 622 AN: 151012 Hom.: 3 Cov.: 24 AF XY: 0.00399 AC XY: 294 AN XY: 73706

African (AFR) AF: 0.0128 AC: 524 AN: 41026

American (AMR) AF: 0.00238 AC: 36 AN: 15154

Ashkenazi Jewish (ASJ) AF: 0.00663 AC: 23 AN: 3468

East Asian (EAS) AF: 0.000396 AC: 2 AN: 5054

South Asian (SAS) AF: 0.000422 AC: 2 AN: 4734

European-Finnish (FIN) AF: 0.000191 AC: 2 AN: 10480

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

European-Non Finnish (NFE) AF: 0.000339 AC: 23 AN: 67802

Other (OTH) AF: 0.00381 AC: 8 AN: 2098

Alfa AF: 0.00107 Hom.: 211

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not provided (6)
-	-	3	not specified (4)
-	-	1	Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G (1)
-	-	1	Cardiomyopathy (1)
-	-	1	TTN-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.6
Mutation Taster		=100/0	polymorphism

Splicing

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: rs71393436;

hg19: chr2-179578108;