2-178540059-A-T

Variant names:

• chr2-178540059-A-T
• rs2288325
• NM_001267550.2:c.98098+9T>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001267550.2(TTN):​c.98098+9T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.157 in 1,595,098 control chromosomes in the GnomAD database, including 22,429 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.16 (2323 hom., cov: 32)
  • Exomes 𝑓: 0.16 (20106 hom.)
• Consequence: TTN NM_001267550.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:17
• Conservation: PhyloP100: -0.660
• Publications: 11 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 2-178540059-A-T is Benign according to our data. Variant chr2-178540059-A-T is described in ClinVar as Benign. ClinVar VariationId is 47594.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.428 is higher than 0.05.

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.98098+9T>A		intron	N/A	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.93175+9T>A		intron	N/A	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.90394+9T>A		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.98098+9T>A		intron	N/A	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.97942+9T>A		intron	N/A	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.97822+9T>A		intron	N/A	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.162 AC: 24683 AN: 152030 Hom.: 2317 Cov.: 32

Gnomad AFR AF: 0.145

Gnomad AMI AF: 0.474

Gnomad AMR AF: 0.136

Gnomad ASJ AF: 0.186

Gnomad EAS AF: 0.443

Gnomad SAS AF: 0.258

Gnomad FIN AF: 0.162

Gnomad MID AF: 0.120

Gnomad NFE AF: 0.146

Gnomad OTH AF: 0.148

GnomAD2 exomes AF: 0.182 AC: 43030 AN: 236586 AF XY: 0.184

Gnomad AFR exome AF: 0.144

Gnomad AMR exome AF: 0.149

Gnomad ASJ exome AF: 0.189

Gnomad EAS exome AF: 0.431

Gnomad FIN exome AF: 0.152

Gnomad NFE exome AF: 0.144

Gnomad OTH exome AF: 0.164

GnomAD4 exome AF: 0.156 AC: 225390 AN: 1442950 Hom.: 20106 Cov.: 34 AF XY: 0.159 AC XY: 113647 AN XY: 715342

African (AFR) AF: 0.143 AC: 4724 AN: 32990

American (AMR) AF: 0.150 AC: 6553 AN: 43644

Ashkenazi Jewish (ASJ) AF: 0.185 AC: 4584 AN: 24818

East Asian (EAS) AF: 0.434 AC: 17151 AN: 39492

South Asian (SAS) AF: 0.250 AC: 20819 AN: 83164

European-Finnish (FIN) AF: 0.151 AC: 7927 AN: 52538

Middle Eastern (MID) AF: 0.131 AC: 744 AN: 5658

European-Non Finnish (NFE) AF: 0.139 AC: 152838 AN: 1101142

Other (OTH) AF: 0.169 AC: 10050 AN: 59504

GnomAD4 genome AF: 0.162 AC: 24698 AN: 152148 Hom.: 2323 Cov.: 32 AF XY: 0.166 AC XY: 12343 AN XY: 74388

African (AFR) AF: 0.145 AC: 6011 AN: 41518

American (AMR) AF: 0.136 AC: 2076 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.186 AC: 645 AN: 3470

East Asian (EAS) AF: 0.443 AC: 2282 AN: 5146

South Asian (SAS) AF: 0.256 AC: 1235 AN: 4818

European-Finnish (FIN) AF: 0.162 AC: 1720 AN: 10598

Middle Eastern (MID) AF: 0.129 AC: 38 AN: 294

European-Non Finnish (NFE) AF: 0.146 AC: 9928 AN: 67988

Other (OTH) AF: 0.157 AC: 332 AN: 2114

Alfa AF: 0.157 Hom.: 380

Bravo AF: 0.161

Asia WGS AF: 0.348 AC: 1210 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	2	Autosomal recessive limb-girdle muscular dystrophy type 2J (2)
-	-	2	Early-onset myopathy with fatal cardiomyopathy (2)
-	-	2	Myopathy, myofibrillar, 9, with early respiratory failure (2)
-	-	2	Tibial muscular dystrophy (2)
-	-	1	Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G (1)
-	-	1	Dilated cardiomyopathy 1G (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.072
DANN	Benign	0.62
PhyloP100		-0.66
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2288325; hg19: chr2-179404786; COSMIC: COSV59894609; COSMIC: COSV59894609;