2-178685543-C-T

Variant names:

• chr2-178685543-C-T
• rs79232842
• NM_001267550.2:c.32367G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_001267550.2(TTN):​c.32367G>A​(p.Lys10789Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000379 in 1,613,562 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0020 (4 hom., cov: 32)
  • Exomes 𝑓: 0.00021 (1 hom.)
• Consequence: TTN NM_001267550.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 0.631
• 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]

LOC124906100 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.3).
• BP6: Variant 2-178685543-C-T is Benign according to our data. Variant chr2-178685543-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 46865.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.631 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.002 (304/152340) while in subpopulation AFR AF = 0.00685 (285/41576). AF 95% confidence interval is 0.0062. There are 4 homozygotes in GnomAd4. There are 151 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 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.32367G>A	p.Lys10789Lys	synonymous	Exon 128 of 363	NP_001254479.2
	TTN	NM_001256850.1		c.31416G>A	p.Lys10472Lys	synonymous	Exon 126 of 313	NP_001243779.1
	TTN	NM_133378.4		c.28635G>A	p.Lys9545Lys	synonymous	Exon 125 of 312	NP_596869.4

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	ENST00000589042.5	TSL:5 MANE Select	c.32367G>A	p.Lys10789Lys	synonymous	Exon 128 of 363	ENSP00000467141.1
	TTN	ENST00000446966.2	TSL:1	c.32367G>A	p.Lys10789Lys	synonymous	Exon 128 of 361	ENSP00000408004.2
	TTN	ENST00000436599.2	TSL:1	c.32091G>A	p.Lys10697Lys	synonymous	Exon 126 of 361	ENSP00000405517.2

Frequencies

GnomAD3 genomes AF: 0.00198 AC: 301 AN: 152222 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00680

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000851

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: 0.0000441

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.000552 AC: 137 AN: 248384 AF XY: 0.000423

Gnomad AFR exome AF: 0.00778

Gnomad AMR exome AF: 0.000377

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000267

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.000210 AC: 307 AN: 1461222 Hom.: 1 Cov.: 31 AF XY: 0.000197 AC XY: 143 AN XY: 726820

African (AFR) AF: 0.00690 AC: 231 AN: 33472

American (AMR) AF: 0.000447 AC: 20 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26116

East Asian (EAS) AF: 0.00 AC: 0 AN: 39662

South Asian (SAS) AF: 0.00 AC: 0 AN: 86086

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53390

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5764

European-Non Finnish (NFE) AF: 0.0000108 AC: 12 AN: 1111686

Other (OTH) AF: 0.000630 AC: 38 AN: 60348

GnomAD4 genome AF: 0.00200 AC: 304 AN: 152340 Hom.: 4 Cov.: 32 AF XY: 0.00203 AC XY: 151 AN XY: 74500

African (AFR) AF: 0.00685 AC: 285 AN: 41576

American (AMR) AF: 0.000850 AC: 13 AN: 15296

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

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

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68034

Other (OTH) AF: 0.00142 AC: 3 AN: 2114

Alfa AF: 0.000921 Hom.: 0

Bravo AF: 0.00222

Asia WGS AF: 0.000867 AC: 3 AN: 3476

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	2	not provided (2)
-	-	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	-0.30
CADD	Benign	6.4
DANN	Benign	0.67
PhyloP100		0.63
Mutation Taster		=96/4	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: rs79232842; hg19: chr2-179550270;