NM_001267550.2:c.22077A>T

Variant names:

• chr2-178722822-T-A
• rs202102237
• NM_001267550.2:c.22077A>T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_001267550.2(TTN):​c.22077A>T​(p.Gly7359Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000849 in 1,613,328 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00049 (2 hom., cov: 33)
  • Exomes 𝑓: 0.00089 (20 hom.)
• Consequence: TTN NM_001267550.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:20
• Conservation: PhyloP100: 1.25
• 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 -16 ACMG points.

• BP6: Variant 2-178722822-T-A is Benign according to our data. Variant chr2-178722822-T-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 46694.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 = 0.000493 (75/152198) while in subpopulation SAS AF = 0.0139 (67/4822). AF 95% confidence interval is 0.0112. There are 2 homozygotes in GnomAd4. There are 54 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 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.22077A>T	p.Gly7359Gly	synonymous	Exon 76 of 363	NP_001254479.2
	TTN	NM_001256850.1		c.21126A>T	p.Gly7042Gly	synonymous	Exon 74 of 313	NP_001243779.1
	TTN	NM_133378.4		c.18345A>T	p.Gly6115Gly	synonymous	Exon 73 of 312	NP_596869.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	ENST00000589042.5	TSL:5 MANE Select	c.22077A>T	p.Gly7359Gly	synonymous	Exon 76 of 363	ENSP00000467141.1
	TTN	ENST00000446966.2	TSL:1	c.22077A>T	p.Gly7359Gly	synonymous	Exon 76 of 361	ENSP00000408004.2
	TTN	ENST00000436599.2	TSL:1	c.21801A>T	p.Gly7267Gly	synonymous	Exon 74 of 361	ENSP00000405517.2

Frequencies

GnomAD3 genomes AF: 0.000500 AC: 76 AN: 152080 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0141

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000883

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00176 AC: 436 AN: 248372 AF XY: 0.00245

Gnomad AFR exome AF: 0.0000646

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000534

Gnomad OTH exome AF: 0.000333

GnomAD4 exome AF: 0.000886 AC: 1294 AN: 1461130 Hom.: 20 Cov.: 34 AF XY: 0.00126 AC XY: 913 AN XY: 726814

African (AFR) AF: 0.0000598 AC: 2 AN: 33448

American (AMR) AF: 0.0000448 AC: 2 AN: 44682

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39668

South Asian (SAS) AF: 0.0137 AC: 1184 AN: 86228

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53340

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.0000531 AC: 59 AN: 1111574

Other (OTH) AF: 0.000779 AC: 47 AN: 60308

GnomAD4 genome AF: 0.000493 AC: 75 AN: 152198 Hom.: 2 Cov.: 33 AF XY: 0.000726 AC XY: 54 AN XY: 74398

African (AFR) AF: 0.0000481 AC: 2 AN: 41568

American (AMR) AF: 0.00 AC: 0 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5162

South Asian (SAS) AF: 0.0139 AC: 67 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

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

European-Non Finnish (NFE) AF: 0.0000883 AC: 6 AN: 67972

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.000174

Asia WGS AF: 0.00376 AC: 13 AN: 3476

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	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	not provided (2)
-	-	2	Tibial muscular dystrophy (2)
-	-	1	Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G (1)
-	-	1	Cardiomyopathy (1)
-	-	1	Dilated cardiomyopathy 1G (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
CADD	Benign	8.9
DANN	Benign	0.64
PhyloP100		1.3
Mutation Taster		=90/10	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.21		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.21		Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs202102237; hg19: chr2-179587549; COSMIC: COSV105217427; COSMIC: COSV105217427;