rs770966939

Variant names:

• chr2-178657970-ATAT-A
• rs770966939
• NM_001267550.2:c.37793-12_37793-10delATA

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP6_Moderate BS2

The NM_001267550.2(TTN):​c.37793-12_37793-10delATA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000644 in 1,087,358 control chromosomes in the GnomAD database, including 3 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000095 (0 hom., cov: 15)
  • Exomes 𝑓: 0.000061 (3 hom.)
• Consequence: TTN NM_001267550.2 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.38
• Publications: 0 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: Likely_benign. The variant received -6 ACMG points.

• BP6: Variant 2-178657970-ATAT-A is Benign according to our data. Variant chr2-178657970-ATAT-A is described in ClinVar as Likely_benign. ClinVar VariationId is 413197.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAdExome4 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.37793-12_37793-10delATA		intron	N/A	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.34522+1032_34522+1034delATA		intron	N/A	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.31741+1032_31741+1034delATA		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.37793-12_37793-10delATA		intron	N/A	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.37793-12_37793-10delATA		intron	N/A	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.37517-12_37517-10delATA		intron	N/A	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.0000945 AC: 10 AN: 105776 Hom.: 0 Cov.: 15

Gnomad AFR AF: 0.0000398

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000165

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000747 AC: 4 AN: 53538 AF XY: 0.000110

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000185

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000611 AC: 60 AN: 981582 Hom.: 3 AF XY: 0.0000662 AC XY: 33 AN XY: 498700

African (AFR) AF: 0.00 AC: 0 AN: 21250

American (AMR) AF: 0.00 AC: 0 AN: 27004

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21666

East Asian (EAS) AF: 0.00 AC: 0 AN: 36014

South Asian (SAS) AF: 0.00 AC: 0 AN: 64202

European-Finnish (FIN) AF: 0.0000290 AC: 1 AN: 34474

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3156

European-Non Finnish (NFE) AF: 0.0000781 AC: 57 AN: 729616

Other (OTH) AF: 0.0000452 AC: 2 AN: 44200

GnomAD4 genome AF: 0.0000945 AC: 10 AN: 105776 Hom.: 0 Cov.: 15 AF XY: 0.0000603 AC XY: 3 AN XY: 49758

African (AFR) AF: 0.0000398 AC: 1 AN: 25144

American (AMR) AF: 0.00 AC: 0 AN: 8314

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2836

East Asian (EAS) AF: 0.00 AC: 0 AN: 3908

South Asian (SAS) AF: 0.00 AC: 0 AN: 2662

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6244

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 234

European-Non Finnish (NFE) AF: 0.000165 AC: 9 AN: 54534

Other (OTH) AF: 0.00 AC: 0 AN: 1422

Alfa AF: 0.000184 Hom.: 1

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.4
Mutation Taster		=87/13	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs770966939;

hg19: chr2-179522697;