rs200847757

Variant names:

• chr2-178550286-G-A
• rs200847757
• NM_001267550.2:c.91565-13C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-178550286-G-A
• chr2-178550286-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001267550.2(TTN):​c.91565-13C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00212 in 1,596,012 control chromosomes in the GnomAD database, including 52 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0018 (5 hom., cov: 33)
  • Exomes 𝑓: 0.0022 (47 hom.)
• Consequence: TTN NM_001267550.2 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:22
• Conservation: PhyloP100: -1.99
• 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]

ENSG00000270277 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 2-178550286-G-A is Benign according to our data. Variant chr2-178550286-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 47510.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00179 (273/152192) while in subpopulation SAS AF = 0.0239 (115/4820). AF 95% confidence interval is 0.0203. There are 5 homozygotes in GnomAd4. There are 153 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	NM_001267550.2	MANE Select	c.91565-13C>T		intron	N/A	NP_001254479.2
	TTN	NM_001256850.1		c.86642-13C>T		intron	N/A	NP_001243779.1
	TTN	NM_133378.4		c.83861-13C>T		intron	N/A	NP_596869.4

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	ENST00000589042.5	TSL:5 MANE Select	c.91565-13C>T		intron	N/A	ENSP00000467141.1
	TTN	ENST00000446966.2	TSL:1	c.91409-13C>T		intron	N/A	ENSP00000408004.2
	TTN	ENST00000436599.2	TSL:1	c.91289-13C>T		intron	N/A	ENSP00000405517.2

Frequencies

GnomAD3 genomes AF: 0.00178 AC: 270 AN: 152074 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00184

Gnomad ASJ AF: 0.000866

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0232

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00166

Gnomad OTH AF: 0.00192

GnomAD2 exomes AF: 0.00350 AC: 827 AN: 235954 AF XY: 0.00445

Gnomad AFR exome AF: 0.000200

Gnomad AMR exome AF: 0.000769

Gnomad ASJ exome AF: 0.000757

Gnomad EAS exome AF: 0.0000572

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00171

Gnomad OTH exome AF: 0.00372

GnomAD4 exome AF: 0.00216 AC: 3112 AN: 1443820 Hom.: 47 Cov.: 30 AF XY: 0.00274 AC XY: 1966 AN XY: 717004

African (AFR) AF: 0.000367 AC: 12 AN: 32658

American (AMR) AF: 0.000678 AC: 29 AN: 42786

Ashkenazi Jewish (ASJ) AF: 0.000785 AC: 20 AN: 25484

East Asian (EAS) AF: 0.000152 AC: 6 AN: 39500

South Asian (SAS) AF: 0.0205 AC: 1726 AN: 84180

European-Finnish (FIN) AF: 0.0000788 AC: 4 AN: 50730

Middle Eastern (MID) AF: 0.00423 AC: 24 AN: 5670

European-Non Finnish (NFE) AF: 0.00101 AC: 1114 AN: 1103184

Other (OTH) AF: 0.00297 AC: 177 AN: 59628

GnomAD4 genome AF: 0.00179 AC: 273 AN: 152192 Hom.: 5 Cov.: 33 AF XY: 0.00206 AC XY: 153 AN XY: 74390

African (AFR) AF: 0.000241 AC: 10 AN: 41524

American (AMR) AF: 0.00183 AC: 28 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.000866 AC: 3 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.0239 AC: 115 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10596

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

European-Non Finnish (NFE) AF: 0.00166 AC: 113 AN: 68026

Other (OTH) AF: 0.00190 AC: 4 AN: 2108

Alfa AF: 0.00125 Hom.: 1

Bravo AF: 0.00104

Asia WGS AF: 0.0130 AC: 46 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	-	4	not provided (4)
-	-	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	-0.84
CADD	Benign	0.017
DANN	Benign	0.42
PhyloP100		-2.0
Mutation Taster		=100/0	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: rs200847757; hg19: chr2-179415013;