rs201770959

Variant names:

• chr2-178557559-C-A
• rs201770959
• NM_001267550.2:c.87707-4G>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001267550.2(TTN):​c.87707-4G>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00276 in 1,609,070 control chromosomes in the GnomAD database, including 14 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0019 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0028 (13 hom.)
• Consequence: TTN NM_001267550.2 splice_region, intron
• Scores: Splicing: ADA: 0.00007390
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:19
• Conservation: PhyloP100: -0.832
• Publications: 1 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]

ENSG00000279598 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 2-178557559-C-A is Benign according to our data. Variant chr2-178557559-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 96312.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00193 (286/148334) while in subpopulation NFE AF = 0.00302 (201/66602). AF 95% confidence interval is 0.00268. There are 1 homozygotes in GnomAd4. There are 139 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 13 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.87707-4G>T		splice_region intron	N/A	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.82784-4G>T		splice_region intron	N/A	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.80003-4G>T		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.87707-4G>T		splice_region intron	N/A	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.87551-4G>T		splice_region intron	N/A	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.87431-4G>T		splice_region intron	N/A	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.00193 AC: 286 AN: 148212 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000576

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00267

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000202

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00143

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00302

Gnomad OTH AF: 0.00298

GnomAD2 exomes AF: 0.00175 AC: 435 AN: 248568 AF XY: 0.00172

Gnomad AFR exome AF: 0.000581

Gnomad AMR exome AF: 0.00165

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000696

Gnomad NFE exome AF: 0.00301

Gnomad OTH exome AF: 0.00249

GnomAD4 exome AF: 0.00285 AC: 4163 AN: 1460736 Hom.: 13 Cov.: 33 AF XY: 0.00268 AC XY: 1950 AN XY: 726624

African (AFR) AF: 0.000568 AC: 19 AN: 33458

American (AMR) AF: 0.00148 AC: 66 AN: 44534

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39646

South Asian (SAS) AF: 0.0000465 AC: 4 AN: 86058

European-Finnish (FIN) AF: 0.00105 AC: 56 AN: 53394

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00350 AC: 3885 AN: 1111422

Other (OTH) AF: 0.00219 AC: 132 AN: 60338

GnomAD4 genome AF: 0.00193 AC: 286 AN: 148334 Hom.: 1 Cov.: 33 AF XY: 0.00191 AC XY: 139 AN XY: 72604

African (AFR) AF: 0.000574 AC: 23 AN: 40066

American (AMR) AF: 0.00267 AC: 40 AN: 14988

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3388

East Asian (EAS) AF: 0.000203 AC: 1 AN: 4930

South Asian (SAS) AF: 0.00 AC: 0 AN: 4648

European-Finnish (FIN) AF: 0.00143 AC: 15 AN: 10478

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00302 AC: 201 AN: 66602

Other (OTH) AF: 0.00294 AC: 6 AN: 2038

Alfa AF: 0.00221 Hom.: 0

Bravo AF: 0.00179

EpiCase AF: 0.00251

EpiControl AF: 0.00267

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	-	6	not provided (6)
-	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	Cardiovascular phenotype (1)
-	1	-	Dilated cardiomyopathy 1G (1)
-	1	-	Early-onset myopathy with fatal 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
BayesDel_noAF	Benign	-0.82
CADD	Benign	2.6
DANN	Benign	0.68
PhyloP100		-0.83
Mutation Taster		=91/9	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000074
dbscSNV1_RF	Benign	0.044
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: rs201770959; hg19: chr2-179422286;