chr2-178608098-T-C

Variant names:

• chr2-178608098-T-C
• rs72646807
• NM_001267550.2:c.52706-17A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001267550.2(TTN):​c.52706-17A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0194 in 1,609,572 control chromosomes in the GnomAD database, including 405 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (29 hom., cov: 33)
  • Exomes 𝑓: 0.020 (376 hom.)
• Consequence: TTN NM_001267550.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: -1.55
• Publications: 2 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]

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 2-178608098-T-C is Benign according to our data. Variant chr2-178608098-T-C is described in ClinVar as Benign. ClinVar VariationId is 137796.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0805 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.52706-17A>G		intron	N/A	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.47783-17A>G		intron	N/A	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.45002-17A>G		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.52706-17A>G		intron	N/A	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.52550-17A>G		intron	N/A	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.52430-17A>G		intron	N/A	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.0154 AC: 2339 AN: 151996 Hom.: 29 Cov.: 33

Gnomad AFR AF: 0.00418

Gnomad AMI AF: 0.00549

Gnomad AMR AF: 0.0225

Gnomad ASJ AF: 0.0447

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.00704

Gnomad FIN AF: 0.00273

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.0222

Gnomad OTH AF: 0.0334

GnomAD2 exomes AF: 0.0165 AC: 3970 AN: 240484 AF XY: 0.0171

Gnomad AFR exome AF: 0.00383

Gnomad AMR exome AF: 0.0191

Gnomad ASJ exome AF: 0.0373

Gnomad EAS exome AF: 0.0000584

Gnomad FIN exome AF: 0.00372

Gnomad NFE exome AF: 0.0225

Gnomad OTH exome AF: 0.0265

GnomAD4 exome AF: 0.0198 AC: 28829 AN: 1457458 Hom.: 376 Cov.: 32 AF XY: 0.0198 AC XY: 14332 AN XY: 724736

African (AFR) AF: 0.00424 AC: 141 AN: 33284

American (AMR) AF: 0.0203 AC: 896 AN: 44068

Ashkenazi Jewish (ASJ) AF: 0.0375 AC: 977 AN: 26028

East Asian (EAS) AF: 0.0000509 AC: 2 AN: 39302

South Asian (SAS) AF: 0.00782 AC: 672 AN: 85902

European-Finnish (FIN) AF: 0.00331 AC: 176 AN: 53222

Middle Eastern (MID) AF: 0.0868 AC: 499 AN: 5746

European-Non Finnish (NFE) AF: 0.0218 AC: 24188 AN: 1109758

Other (OTH) AF: 0.0212 AC: 1278 AN: 60148

GnomAD4 genome AF: 0.0154 AC: 2337 AN: 152114 Hom.: 29 Cov.: 33 AF XY: 0.0149 AC XY: 1111 AN XY: 74342

African (AFR) AF: 0.00416 AC: 173 AN: 41558

American (AMR) AF: 0.0225 AC: 343 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.0447 AC: 155 AN: 3470

East Asian (EAS) AF: 0.000195 AC: 1 AN: 5130

South Asian (SAS) AF: 0.00684 AC: 33 AN: 4824

European-Finnish (FIN) AF: 0.00273 AC: 29 AN: 10624

Middle Eastern (MID) AF: 0.0748 AC: 22 AN: 294

European-Non Finnish (NFE) AF: 0.0222 AC: 1507 AN: 67930

Other (OTH) AF: 0.0326 AC: 69 AN: 2116

Alfa AF: 0.0226 Hom.: 23

Bravo AF: 0.0162

Asia WGS AF: 0.00318 AC: 11 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	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	Tibial muscular dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.15
DANN	Benign	0.58
PhyloP100		-1.6
Mutation Taster		=100/0	polymorphism (auto)

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: rs72646807; hg19: chr2-179472825;