2-178653276-A-G

Variant names:

• chr2-178653276-A-G
• rs2562847
• NM_001267550.2:c.38753T>C

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.38753T>C​(p.Leu12918Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0686 in 151,694 control chromosomes in the GnomAD database, including 531 homozygotes. In-silico tool predicts a benign outcome for this variant. 9/11 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L12918W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.069 (531 hom., cov: 29)
  • Exomes 𝑓: 0.064 (4827 hom.)
  • Failed GnomAD Quality Control
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -1.21
• Publications: 8 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0048615634).
• BP6: Variant 2-178653276-A-G is Benign according to our data. Variant chr2-178653276-A-G is described in ClinVar as Benign. ClinVar VariationId is 535163.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.178 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.38753T>C	p.Leu12918Ser	missense	Exon 198 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.34523-735T>C		intron	N/A	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.31742-735T>C		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.38753T>C	p.Leu12918Ser	missense	Exon 198 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.38753T>C	p.Leu12918Ser	missense	Exon 198 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.38477T>C	p.Leu12826Ser	missense	Exon 196 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.0686 AC: 10391 AN: 151574 Hom.: 525 Cov.: 29

Gnomad AFR AF: 0.0432

Gnomad AMI AF: 0.0727

Gnomad AMR AF: 0.160

Gnomad ASJ AF: 0.0449

Gnomad EAS AF: 0.119

Gnomad SAS AF: 0.189

Gnomad FIN AF: 0.101

Gnomad MID AF: 0.0484

Gnomad NFE AF: 0.0478

Gnomad OTH AF: 0.0567

GnomAD2 exomes AF: 0.102 AC: 25221 AN: 246724 AF XY: 0.101

Gnomad AFR exome AF: 0.0434

Gnomad AMR exome AF: 0.224

Gnomad ASJ exome AF: 0.0420

Gnomad EAS exome AF: 0.129

Gnomad FIN exome AF: 0.104

Gnomad NFE exome AF: 0.0492

Gnomad OTH exome AF: 0.0842

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0637 AC: 92795 AN: 1457244 Hom.: 4827 Cov.: 34 AF XY: 0.0666 AC XY: 48253 AN XY: 725010

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0425 AC: 1419 AN: 33356

American (AMR) AF: 0.217 AC: 9584 AN: 44204

Ashkenazi Jewish (ASJ) AF: 0.0410 AC: 1069 AN: 26082

East Asian (EAS) AF: 0.107 AC: 4252 AN: 39644

South Asian (SAS) AF: 0.186 AC: 15941 AN: 85812

European-Finnish (FIN) AF: 0.107 AC: 5717 AN: 53290

Middle Eastern (MID) AF: 0.0459 AC: 244 AN: 5320

European-Non Finnish (NFE) AF: 0.0456 AC: 50548 AN: 1109366

Other (OTH) AF: 0.0668 AC: 4021 AN: 60170

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0686 AC: 10406 AN: 151694 Hom.: 531 Cov.: 29 AF XY: 0.0753 AC XY: 5583 AN XY: 74106

African (AFR) AF: 0.0432 AC: 1790 AN: 41452

American (AMR) AF: 0.161 AC: 2432 AN: 15130

Ashkenazi Jewish (ASJ) AF: 0.0449 AC: 156 AN: 3472

East Asian (EAS) AF: 0.120 AC: 614 AN: 5120

South Asian (SAS) AF: 0.189 AC: 899 AN: 4766

European-Finnish (FIN) AF: 0.101 AC: 1070 AN: 10554

Middle Eastern (MID) AF: 0.0448 AC: 13 AN: 290

European-Non Finnish (NFE) AF: 0.0478 AC: 3248 AN: 67898

Other (OTH) AF: 0.0561 AC: 118 AN: 2104

Alfa AF: 0.0325 Hom.: 28

ExAC AF: 0.0965 AC: 11621

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (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_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	0.12
DANN	Benign	0.53
FATHMM_MKL	Benign	0.080	N
LIST_S2	Benign	0.17	T
MetaRNN	Benign	0.0049	T
PhyloP100		-1.2
Vest4		0.024
GERP RS		-2.6
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs2562847; hg19: chr2-179518003; COSMIC: COSV60268279; COSMIC: COSV60268279;