2-178741863-T-C

Variant names:

• chr2-178741863-T-C
• rs72648918
• NM_001267550.2:c.11370A>G

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_001267550.2(TTN):​c.11370A>G​(p.Gln3790Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000584 in 1,591,386 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0013 (3 hom., cov: 33)
  • Exomes 𝑓: 0.00051 (1 hom.)
• Consequence: TTN NM_001267550.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:20
• Conservation: PhyloP100: -0.185
• 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]

ACMG classification

Our verdict: Benign. The variant received -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 2-178741863-T-C is Benign according to our data. Variant chr2-178741863-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 137834.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.185 with no splicing effect.
• BS2: High Homozygotes in GnomAd4 at 3 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.11370A>G	p.Gln3790Gln	synonymous	Exon 48 of 363	NP_001254479.2
	TTN	NM_001256850.1		c.10419A>G	p.Gln3473Gln	synonymous	Exon 46 of 313	NP_001243779.1
	TTN	NM_133437.4		c.10857A>G	p.Gln3619Gln	synonymous	Exon 46 of 192	NP_597681.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	ENST00000589042.5	TSL:5 MANE Select	c.11370A>G	p.Gln3790Gln	synonymous	Exon 48 of 363	ENSP00000467141.1
	TTN	ENST00000446966.2	TSL:1	c.11370A>G	p.Gln3790Gln	synonymous	Exon 48 of 361	ENSP00000408004.2
	TTN	ENST00000436599.2	TSL:1	c.11094A>G	p.Gln3698Gln	synonymous	Exon 46 of 361	ENSP00000405517.2

Frequencies

GnomAD3 genomes AF: 0.00130 AC: 197 AN: 152116 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.000265

Gnomad AMI AF: 0.112

Gnomad AMR AF: 0.00151

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000853

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.000504 AC: 106 AN: 210350 AF XY: 0.000484

Gnomad AFR exome AF: 0.000161

Gnomad AMR exome AF: 0.000954

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000806

Gnomad OTH exome AF: 0.000373

GnomAD4 exome AF: 0.000509 AC: 732 AN: 1439152 Hom.: 1 Cov.: 32 AF XY: 0.000510 AC XY: 364 AN XY: 714026

African (AFR) AF: 0.000151 AC: 5 AN: 33050

American (AMR) AF: 0.00133 AC: 54 AN: 40462

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25774

East Asian (EAS) AF: 0.00 AC: 0 AN: 38708

South Asian (SAS) AF: 0.00 AC: 0 AN: 83670

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51990

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5734

European-Non Finnish (NFE) AF: 0.000596 AC: 656 AN: 1100154

Other (OTH) AF: 0.000285 AC: 17 AN: 59610

GnomAD4 genome AF: 0.00129 AC: 197 AN: 152234 Hom.: 3 Cov.: 33 AF XY: 0.00124 AC XY: 92 AN XY: 74452

African (AFR) AF: 0.000265 AC: 11 AN: 41558

American (AMR) AF: 0.00151 AC: 23 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

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

European-Non Finnish (NFE) AF: 0.000853 AC: 58 AN: 68000

Other (OTH) AF: 0.00142 AC: 3 AN: 2112

Alfa AF: 0.000444 Hom.: 0

Bravo AF: 0.00173

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	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	Cardiovascular phenotype (1)
-	-	1	Early-onset myopathy with fatal cardiomyopathy (1)
-	-	1	Myopathy, myofibrillar, 9, with early respiratory failure (1)
-	-	1	Tibial muscular dystrophy (1)
-	-	1	TTN-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.1
DANN	Benign	0.34
PhyloP100		-0.18
Mutation Taster		=98/2	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: rs72648918; hg19: chr2-179606590;