rs201200682

Variant names:

• chr2-178739229-G-A
• rs201200682
• NM_001267550.2:c.14004C>T

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS1

The ENST00000589042.5(TTN):​c.14004C>T​(p.Thr4668Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000594 in 1,581,664 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00050 (0 hom.)
• Consequence: TTN ENST00000589042.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:16
• Conservation: PhyloP100: 1.47
• 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]

LOC124906101 (HGNC:):

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=-0.62).
• BP6: Variant 2-178739229-G-A is Benign according to our data. Variant chr2-178739229-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 47844.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.47 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00145 (220/152166) while in subpopulation AFR AF = 0.00441 (183/41528). AF 95% confidence interval is 0.00388. There are 0 homozygotes in GnomAd4. There are 98 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000589042.5. 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.14004C>T	p.Thr4668Thr	synonymous	Exon 48 of 363	NP_001254479.2
	TTN	NM_001256850.1		c.13053C>T	p.Thr4351Thr	synonymous	Exon 46 of 313	NP_001243779.1
	TTN	NM_133437.4		c.13491C>T	p.Thr4497Thr	synonymous	Exon 46 of 192	NP_597681.4

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	ENST00000589042.5	TSL:5 MANE Select	c.14004C>T	p.Thr4668Thr	synonymous	Exon 48 of 363	ENSP00000467141.1
	TTN	ENST00000446966.2	TSL:1	c.14004C>T	p.Thr4668Thr	synonymous	Exon 48 of 361	ENSP00000408004.2
	TTN	ENST00000436599.2	TSL:1	c.13728C>T	p.Thr4576Thr	synonymous	Exon 46 of 361	ENSP00000405517.2

Frequencies

GnomAD3 genomes AF: 0.00145 AC: 220 AN: 152048 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00442

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000328

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: 0.000427

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.000535 AC: 123 AN: 229938 AF XY: 0.000453

Gnomad AFR exome AF: 0.00424

Gnomad AMR exome AF: 0.000181

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000567

Gnomad FIN exome AF: 0.000250

Gnomad NFE exome AF: 0.000409

Gnomad OTH exome AF: 0.000360

GnomAD4 exome AF: 0.000504 AC: 720 AN: 1429498 Hom.: 0 Cov.: 30 AF XY: 0.000456 AC XY: 322 AN XY: 705958

African (AFR) AF: 0.00459 AC: 151 AN: 32868

American (AMR) AF: 0.000209 AC: 9 AN: 43100

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24212

East Asian (EAS) AF: 0.0000511 AC: 2 AN: 39148

South Asian (SAS) AF: 0.0000248 AC: 2 AN: 80728

European-Finnish (FIN) AF: 0.000211 AC: 11 AN: 52188

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5604

European-Non Finnish (NFE) AF: 0.000469 AC: 512 AN: 1092690

Other (OTH) AF: 0.000560 AC: 33 AN: 58960

GnomAD4 genome AF: 0.00145 AC: 220 AN: 152166 Hom.: 0 Cov.: 32 AF XY: 0.00132 AC XY: 98 AN XY: 74388

African (AFR) AF: 0.00441 AC: 183 AN: 41528

American (AMR) AF: 0.000327 AC: 5 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4804

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

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

European-Non Finnish (NFE) AF: 0.000427 AC: 29 AN: 67986

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

Alfa AF: 0.00111 Hom.: 0

Bravo AF: 0.00154

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	3	not provided (3)
-	-	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	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	-0.62
CADD	Benign	3.0
DANN	Benign	0.81
PhyloP100		1.5
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: rs201200682; hg19: chr2-179603956; COSMIC: COSV60094528; COSMIC: COSV60094528;