rs202032281

Variant names:

• chr2-178661846-A-G
• rs202032281
• NM_001267550.2:c.37202-4T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Moderate BP6_Very_Strong BS2

The NM_001267550.2(TTN):​c.37202-4T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. 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 0.018 (11 hom., cov: 18)
  • Exomes 𝑓: 0.014 (87 hom.)
  • Failed GnomAD Quality Control
• Consequence: TTN NM_001267550.2 splice_region, intron
• Scores: Splicing: ADA: 0.00009880
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -7.49
• Publications: 4 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: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 2-178661846-A-G is Benign according to our data. Variant chr2-178661846-A-G is described in ClinVar as Benign. ClinVar VariationId is 220772.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 11 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.37202-4T>C		splice_region intron	N/A	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.34354+1120T>C		intron	N/A	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.31573+1120T>C		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.37202-4T>C		splice_region intron	N/A	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.37202-4T>C		splice_region intron	N/A	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.36926-4T>C		splice_region intron	N/A	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.0182 AC: 2643 AN: 145286 Hom.: 10 Cov.: 18

Gnomad AFR AF: 0.00430

Gnomad AMI AF: 0.0213

Gnomad AMR AF: 0.0185

Gnomad ASJ AF: 0.0147

Gnomad EAS AF: 0.0782

Gnomad SAS AF: 0.0315

Gnomad FIN AF: 0.0349

Gnomad MID AF: 0.00321

Gnomad NFE AF: 0.0186

Gnomad OTH AF: 0.0175

GnomAD2 exomes AF: 0.0240 AC: 5629 AN: 234670 AF XY: 0.0237

Gnomad AFR exome AF: 0.00410

Gnomad AMR exome AF: 0.0237

Gnomad ASJ exome AF: 0.0120

Gnomad EAS exome AF: 0.0753

Gnomad FIN exome AF: 0.0309

Gnomad NFE exome AF: 0.0190

Gnomad OTH exome AF: 0.0241

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0143 AC: 20336 AN: 1423610 Hom.: 87 Cov.: 31 AF XY: 0.0148 AC XY: 10489 AN XY: 708734

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00275 AC: 89 AN: 32414

American (AMR) AF: 0.0204 AC: 875 AN: 42834

Ashkenazi Jewish (ASJ) AF: 0.00901 AC: 230 AN: 25532

East Asian (EAS) AF: 0.0598 AC: 2232 AN: 37304

South Asian (SAS) AF: 0.0256 AC: 2172 AN: 84988

European-Finnish (FIN) AF: 0.0292 AC: 1490 AN: 50986

Middle Eastern (MID) AF: 0.0110 AC: 50 AN: 4546

European-Non Finnish (NFE) AF: 0.0113 AC: 12270 AN: 1086306

Other (OTH) AF: 0.0158 AC: 928 AN: 58700

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0182 AC: 2642 AN: 145378 Hom.: 11 Cov.: 18 AF XY: 0.0190 AC XY: 1346 AN XY: 70740

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00429 AC: 165 AN: 38482

American (AMR) AF: 0.0185 AC: 272 AN: 14736

Ashkenazi Jewish (ASJ) AF: 0.0147 AC: 50 AN: 3396

East Asian (EAS) AF: 0.0783 AC: 374 AN: 4778

South Asian (SAS) AF: 0.0315 AC: 143 AN: 4538

European-Finnish (FIN) AF: 0.0349 AC: 348 AN: 9970

Middle Eastern (MID) AF: 0.00345 AC: 1 AN: 290

European-Non Finnish (NFE) AF: 0.0186 AC: 1235 AN: 66276

Other (OTH) AF: 0.0173 AC: 35 AN: 2020

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0181 Hom.: 0

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (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 specified (1)
-	-	1	Tibial muscular dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	2.8
DANN	Benign	0.81
PhyloP100		-7.5
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000099
dbscSNV1_RF	Benign	0.12
SpliceAI score (max)		0.090		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: rs202032281; hg19: chr2-179526573; COSMIC: COSV59977990; COSMIC: COSV59977990;