chr2-178549978-A-T

Variant names:

• chr2-178549978-A-T
• rs56145100
• NM_001267550.2:c.91852+8T>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.91852+8T>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0228 in 1,596,054 control chromosomes in the GnomAD database, including 514 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.020 (50 hom., cov: 33)
  • Exomes 𝑓: 0.023 (464 hom.)
• Consequence: TTN NM_001267550.2 splice_region, intron
• Scores: Splicing: ADA: 0.00002437
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:23
• Conservation: PhyloP100: -0.221
• Publications: 6 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]

ENSG00000270277 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 2-178549978-A-T is Benign according to our data. Variant chr2-178549978-A-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 47515.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0556 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.91852+8T>A		splice_region intron	N/A	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.86929+8T>A		splice_region intron	N/A	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.84148+8T>A		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.91852+8T>A		splice_region intron	N/A	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.91696+8T>A		splice_region intron	N/A	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.91576+8T>A		splice_region intron	N/A	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.0202 AC: 3076 AN: 152198 Hom.: 50 Cov.: 33

Gnomad AFR AF: 0.00451

Gnomad AMI AF: 0.0307

Gnomad AMR AF: 0.0217

Gnomad ASJ AF: 0.0190

Gnomad EAS AF: 0.0610

Gnomad SAS AF: 0.00807

Gnomad FIN AF: 0.0447

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0234

Gnomad OTH AF: 0.0191

GnomAD2 exomes AF: 0.0261 AC: 6222 AN: 238298 AF XY: 0.0248

Gnomad AFR exome AF: 0.00464

Gnomad AMR exome AF: 0.0338

Gnomad ASJ exome AF: 0.0142

Gnomad EAS exome AF: 0.0616

Gnomad FIN exome AF: 0.0471

Gnomad NFE exome AF: 0.0233

Gnomad OTH exome AF: 0.0263

GnomAD4 exome AF: 0.0231 AC: 33338 AN: 1443738 Hom.: 464 Cov.: 32 AF XY: 0.0227 AC XY: 16260 AN XY: 715492

African (AFR) AF: 0.00397 AC: 130 AN: 32776

American (AMR) AF: 0.0317 AC: 1369 AN: 43206

Ashkenazi Jewish (ASJ) AF: 0.0142 AC: 359 AN: 25352

East Asian (EAS) AF: 0.0615 AC: 2421 AN: 39388

South Asian (SAS) AF: 0.00656 AC: 550 AN: 83780

European-Finnish (FIN) AF: 0.0483 AC: 2555 AN: 52894

Middle Eastern (MID) AF: 0.00968 AC: 55 AN: 5680

European-Non Finnish (NFE) AF: 0.0223 AC: 24606 AN: 1101190

Other (OTH) AF: 0.0217 AC: 1293 AN: 59472

GnomAD4 genome AF: 0.0202 AC: 3073 AN: 152316 Hom.: 50 Cov.: 33 AF XY: 0.0207 AC XY: 1538 AN XY: 74472

African (AFR) AF: 0.00450 AC: 187 AN: 41574

American (AMR) AF: 0.0217 AC: 332 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0190 AC: 66 AN: 3470

East Asian (EAS) AF: 0.0611 AC: 317 AN: 5186

South Asian (SAS) AF: 0.00745 AC: 36 AN: 4830

European-Finnish (FIN) AF: 0.0447 AC: 475 AN: 10616

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0234 AC: 1590 AN: 68030

Other (OTH) AF: 0.0189 AC: 40 AN: 2114

Alfa AF: 0.0200 Hom.: 10

Bravo AF: 0.0185

Asia WGS AF: 0.0280 AC: 96 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	10	not specified (10)
-	-	3	not provided (3)
-	-	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)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	6.9
DANN	Benign	0.73
PhyloP100		-0.22
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000024
dbscSNV1_RF	Benign	0.11
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: rs56145100; hg19: chr2-179414705; COSMIC: COSV60085025; COSMIC: COSV60085025;