2-178720666-A-G

Variant names:

• chr2-178720666-A-G
• rs2562830
• NM_001267550.2:c.23099-3T>C

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_001267550.2(TTN):​c.23099-3T>C variant causes a splice region, intron change. The variant allele was found at a frequency of 0.247 in 1,567,300 control chromosomes in the GnomAD database, including 57,241 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.32 (9126 hom., cov: 32)
  • Exomes 𝑓: 0.24 (48115 hom.)
• Consequence: TTN NM_001267550.2 splice_region, intron
• Scores: Splicing: ADA: 0.00005692
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:22
• Conservation: PhyloP100: 5.19
• Publications: 17 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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.34).
• BP6: Variant 2-178720666-A-G is Benign according to our data. Variant chr2-178720666-A-G is described in ClinVar as Benign. ClinVar VariationId is 46710.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.633 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.23099-3T>C		splice_region intron	N/A	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.22148-3T>C		splice_region intron	N/A	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.19367-3T>C		splice_region 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.23099-3T>C		splice_region intron	N/A	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.23099-3T>C		splice_region intron	N/A	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.22823-3T>C		splice_region intron	N/A	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.318 AC: 48237 AN: 151756 Hom.: 9088 Cov.: 32

Gnomad AFR AF: 0.468

Gnomad AMI AF: 0.545

Gnomad AMR AF: 0.364

Gnomad ASJ AF: 0.189

Gnomad EAS AF: 0.652

Gnomad SAS AF: 0.431

Gnomad FIN AF: 0.204

Gnomad MID AF: 0.203

Gnomad NFE AF: 0.206

Gnomad OTH AF: 0.292

GnomAD2 exomes AF: 0.309 AC: 63924 AN: 207162 AF XY: 0.301

Gnomad AFR exome AF: 0.476

Gnomad AMR exome AF: 0.408

Gnomad ASJ exome AF: 0.186

Gnomad EAS exome AF: 0.666

Gnomad FIN exome AF: 0.204

Gnomad NFE exome AF: 0.204

Gnomad OTH exome AF: 0.272

GnomAD4 exome AF: 0.240 AC: 339346 AN: 1415426 Hom.: 48115 Cov.: 35 AF XY: 0.243 AC XY: 170176 AN XY: 701290

African (AFR) AF: 0.476 AC: 14764 AN: 31030

American (AMR) AF: 0.404 AC: 13830 AN: 34264

Ashkenazi Jewish (ASJ) AF: 0.184 AC: 4357 AN: 23656

East Asian (EAS) AF: 0.648 AC: 25463 AN: 39272

South Asian (SAS) AF: 0.420 AC: 32541 AN: 77566

European-Finnish (FIN) AF: 0.203 AC: 10282 AN: 50538

Middle Eastern (MID) AF: 0.269 AC: 1475 AN: 5482

European-Non Finnish (NFE) AF: 0.202 AC: 221282 AN: 1095342

Other (OTH) AF: 0.263 AC: 15352 AN: 58276

GnomAD4 genome AF: 0.318 AC: 48329 AN: 151874 Hom.: 9126 Cov.: 32 AF XY: 0.324 AC XY: 24049 AN XY: 74212

African (AFR) AF: 0.468 AC: 19376 AN: 41360

American (AMR) AF: 0.365 AC: 5568 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.189 AC: 654 AN: 3468

East Asian (EAS) AF: 0.652 AC: 3354 AN: 5148

South Asian (SAS) AF: 0.429 AC: 2065 AN: 4808

European-Finnish (FIN) AF: 0.204 AC: 2154 AN: 10570

Middle Eastern (MID) AF: 0.207 AC: 61 AN: 294

European-Non Finnish (NFE) AF: 0.206 AC: 13980 AN: 67944

Other (OTH) AF: 0.295 AC: 622 AN: 2112

Alfa AF: 0.269 Hom.: 2170

Bravo AF: 0.339

Asia WGS AF: 0.538 AC: 1873 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	9	not specified (9)
-	-	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	not provided (2)
-	-	2	Tibial muscular dystrophy (2)
-	-	1	Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Dilated cardiomyopathy 1G (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.34
CADD	Benign	11
DANN	Benign	0.83
PhyloP100		5.2
Mutation Taster		=79/21	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000057
dbscSNV1_RF	Benign	0.016
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: rs2562830; hg19: chr2-179585393; COSMIC: COSV60101799; COSMIC: COSV60101799;