2-178698916-TAAAAAAAAAA-TAAAAAAAAAAA

Variant names:

• chr2-178698916-T-TA
• rs368277751
• NM_001267550.2:c.30683-3dupT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_001267550.2(TTN):​c.30683-3dupT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0908 in 1,262,662 control chromosomes in the GnomAD database, including 152 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.060 (125 hom., cov: 30)
  • Exomes 𝑓: 0.093 (27 hom.)
• Consequence: TTN NM_001267550.2 splice_region, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 0.401
• Publications: 3 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 -16 ACMG points.

• BP6: Variant 2-178698916-T-TA is Benign according to our data. Variant chr2-178698916-T-TA is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 281162.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0881 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.30683-3dupT		splice_region intron	N/A	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.29732-3dupT		splice_region intron	N/A	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.26951-3dupT		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.30683-3_30683-2insT		splice_region intron	N/A	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.30683-3_30683-2insT		splice_region intron	N/A	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.30407-3_30407-2insT		splice_region intron	N/A	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.0598 AC: 5085 AN: 85034 Hom.: 125 Cov.: 30

Gnomad AFR AF: 0.0200

Gnomad AMI AF: 0.0115

Gnomad AMR AF: 0.0568

Gnomad ASJ AF: 0.0431

Gnomad EAS AF: 0.00323

Gnomad SAS AF: 0.00550

Gnomad FIN AF: 0.0603

Gnomad MID AF: 0.0329

Gnomad NFE AF: 0.0905

Gnomad OTH AF: 0.0646

GnomAD2 exomes AF: 0.0748 AC: 4922 AN: 65808 AF XY: 0.0724

Gnomad AFR exome AF: 0.0702

Gnomad AMR exome AF: 0.0767

Gnomad ASJ exome AF: 0.0465

Gnomad EAS exome AF: 0.0836

Gnomad FIN exome AF: 0.0478

Gnomad NFE exome AF: 0.0928

Gnomad OTH exome AF: 0.0837

GnomAD4 exome AF: 0.0930 AC: 109555 AN: 1177608 Hom.: 27 Cov.: 0 AF XY: 0.0911 AC XY: 52963 AN XY: 581680

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

African (AFR) AF: 0.0531 AC: 1324 AN: 24926

American (AMR) AF: 0.0632 AC: 1276 AN: 20180

Ashkenazi Jewish (ASJ) AF: 0.0558 AC: 1158 AN: 20760

East Asian (EAS) AF: 0.0410 AC: 1289 AN: 31460

South Asian (SAS) AF: 0.0561 AC: 3323 AN: 59248

European-Finnish (FIN) AF: 0.0650 AC: 2096 AN: 32222

Middle Eastern (MID) AF: 0.0507 AC: 202 AN: 3984

European-Non Finnish (NFE) AF: 0.101 AC: 94887 AN: 935602

Other (OTH) AF: 0.0813 AC: 4000 AN: 49226

⚠️ 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: 0.0598 AC: 5084 AN: 85054 Hom.: 125 Cov.: 30 AF XY: 0.0557 AC XY: 2260 AN XY: 40608

African (AFR) AF: 0.0199 AC: 430 AN: 21574

American (AMR) AF: 0.0567 AC: 450 AN: 7932

Ashkenazi Jewish (ASJ) AF: 0.0431 AC: 91 AN: 2110

East Asian (EAS) AF: 0.00325 AC: 10 AN: 3078

South Asian (SAS) AF: 0.00553 AC: 16 AN: 2894

European-Finnish (FIN) AF: 0.0603 AC: 264 AN: 4376

Middle Eastern (MID) AF: 0.0352 AC: 5 AN: 142

European-Non Finnish (NFE) AF: 0.0905 AC: 3743 AN: 41350

Other (OTH) AF: 0.0641 AC: 69 AN: 1076

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	not provided (2)
-	-	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	Cardiomyopathy (1)
-	-	1	Early-onset myopathy with fatal cardiomyopathy (1)
-	-	1	Hypertrophic cardiomyopathy (1)
-	-	1	Myopathy, myofibrillar, 9, with early respiratory failure (1)
-	-	1	Tibial muscular dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.40
Mutation Taster		=99/1	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: rs368277751; hg19: chr2-179563643; COSMIC: COSV60060598; COSMIC: COSV60060598;