rs771419718

Variant names:

• chr2-178684899-AAT-A
• rs771419718
• NM_001267550.2:c.32554+5_32554+6delAT

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP6

The NM_001267550.2(TTN):​c.32554+5_32554+6delAT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000315 in 1,597,132 control chromosomes in the GnomAD database, including 1 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00015 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00033 (1 hom.)
• Consequence: TTN NM_001267550.2 splice_region, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:5
• Conservation: PhyloP100: 0.709
• Publications: 0 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: Likely_benign. The variant received -1 ACMG points.

• BP6: Variant 2-178684899-AAT-A is Benign according to our data. Variant chr2-178684899-AAT-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 467017.

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.32554+5_32554+6delAT		splice_region intron	N/A	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.31603+5_31603+6delAT		splice_region intron	N/A	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.28822+5_28822+6delAT		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.32554+5_32554+6delAT		splice_region intron	N/A	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.32554+5_32554+6delAT		splice_region intron	N/A	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.32278+5_32278+6delAT		splice_region intron	N/A	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.000151 AC: 23 AN: 152154 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000166 AC: 38 AN: 228836 AF XY: 0.000202

Gnomad AFR exome AF: 0.000146

Gnomad AMR exome AF: 0.0000308

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000332

Gnomad OTH exome AF: 0.000178

GnomAD4 exome AF: 0.000332 AC: 480 AN: 1444978 Hom.: 1 AF XY: 0.000306 AC XY: 220 AN XY: 717812

African (AFR) AF: 0.0000916 AC: 3 AN: 32754

American (AMR) AF: 0.0000702 AC: 3 AN: 42726

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25522

East Asian (EAS) AF: 0.00 AC: 0 AN: 39572

South Asian (SAS) AF: 0.00 AC: 0 AN: 83478

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52816

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5732

European-Non Finnish (NFE) AF: 0.000415 AC: 458 AN: 1102738

Other (OTH) AF: 0.000268 AC: 16 AN: 59640

GnomAD4 genome AF: 0.000151 AC: 23 AN: 152154 Hom.: 0 Cov.: 32 AF XY: 0.000148 AC XY: 11 AN XY: 74346

African (AFR) AF: 0.000145 AC: 6 AN: 41448

American (AMR) AF: 0.0000654 AC: 1 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000206 AC: 14 AN: 67992

Other (OTH) AF: 0.000478 AC: 1 AN: 2090

Alfa AF: 0.000217 Hom.: 0

Bravo AF: 0.000204

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	4	not provided (5)
-	1	-	Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G (1)
-	1	-	Cardiomyopathy (1)
-	1	-	Myopathy;C1837342:Autosomal recessive limb-girdle muscular dystrophy type 2J;C1838244:Tibial muscular dystrophy;C1858763:Dilated cardiomyopathy 1G;C1863599:Myopathy, myofibrillar, 9, with early respiratory failure;C2673677:Early-onset myopathy with fatal cardiomyopathy (1)
-	-	1	TTN-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.71
Mutation Taster		=88/12	polymorphism

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs771419718;

hg19: chr2-179549626;