2-178766630-TAAA-TAA

Variant names:

• chr2-178766630-TA-T
• rs201990196
• NM_001267550.2:c.9472-19delT

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.9472-19delT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000624 in 1,593,290 control chromosomes in the GnomAD database, including 4 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0020 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00048 (3 hom.)
• Consequence: TTN NM_001267550.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 1.44
• Publications: 1 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 2-178766630-TA-T is Benign according to our data. Variant chr2-178766630-TA-T is described in ClinVar as Benign. ClinVar VariationId is 202287.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 = 0.002 (302/151050) while in subpopulation AFR AF = 0.00583 (240/41184). AF 95% confidence interval is 0.00522. There are 1 homozygotes in GnomAd4. There are 132 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• 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.9472-19delT		intron	N/A	NP_001254479.2
	TTN	NM_001256850.1		c.9472-19delT		intron	N/A	NP_001243779.1
	TTN	NM_133378.4		c.9472-19delT		intron	N/A	NP_596869.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	ENST00000589042.5	TSL:5 MANE Select	c.9472-19delT		intron	N/A	ENSP00000467141.1
	TTN	ENST00000446966.2	TSL:1	c.9472-19delT		intron	N/A	ENSP00000408004.2
	TTN	ENST00000436599.2	TSL:1	c.9196-19delT		intron	N/A	ENSP00000405517.2

Frequencies

GnomAD3 genomes AF: 0.00200 AC: 302 AN: 150948 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00584

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00155

Gnomad ASJ AF: 0.00606

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00108

Gnomad FIN AF: 0.0000949

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.00101 AC: 247 AN: 244338 AF XY: 0.000854

Gnomad AFR exome AF: 0.00632

Gnomad AMR exome AF: 0.000825

Gnomad ASJ exome AF: 0.00541

Gnomad EAS exome AF: 0.000276

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000180

Gnomad OTH exome AF: 0.00117

GnomAD4 exome AF: 0.000481 AC: 693 AN: 1442240 Hom.: 3 Cov.: 27 AF XY: 0.000473 AC XY: 340 AN XY: 718716

African (AFR) AF: 0.00626 AC: 207 AN: 33052

American (AMR) AF: 0.000808 AC: 36 AN: 44530

Ashkenazi Jewish (ASJ) AF: 0.00435 AC: 113 AN: 25988

East Asian (EAS) AF: 0.000406 AC: 16 AN: 39428

South Asian (SAS) AF: 0.000851 AC: 73 AN: 85782

European-Finnish (FIN) AF: 0.0000189 AC: 1 AN: 52952

Middle Eastern (MID) AF: 0.000718 AC: 4 AN: 5570

European-Non Finnish (NFE) AF: 0.000162 AC: 177 AN: 1095208

Other (OTH) AF: 0.00110 AC: 66 AN: 59730

GnomAD4 genome AF: 0.00200 AC: 302 AN: 151050 Hom.: 1 Cov.: 32 AF XY: 0.00179 AC XY: 132 AN XY: 73730

African (AFR) AF: 0.00583 AC: 240 AN: 41184

American (AMR) AF: 0.00155 AC: 23 AN: 14816

Ashkenazi Jewish (ASJ) AF: 0.00606 AC: 21 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00108 AC: 5 AN: 4624

European-Finnish (FIN) AF: 0.0000949 AC: 1 AN: 10532

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 67934

Other (OTH) AF: 0.00142 AC: 3 AN: 2108

Alfa AF: 0.000619 Hom.: 0

Bravo AF: 0.00222

Asia WGS AF: 0.000877 AC: 3 AN: 3436

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	1	Autosomal recessive limb-girdle muscular dystrophy type 2J (1)
-	-	1	Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G (1)
-	-	1	Early-onset myopathy with fatal cardiomyopathy (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		1.4
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs201990196; hg19: chr2-179631357;