rs201797790

Variant names:

• chr2-178658723-C-T
• rs201797790
• NM_001267550.2:c.37525G>A
• TTN p.Glu12509Lys

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001267550.2(TTN):​c.37525G>A​(p.Glu12509Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00182 in 1,417,624 control chromosomes in the GnomAD database, including 58 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/15 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0012 (4 hom., cov: 19)
  • Exomes 𝑓: 0.0018 (58 hom.)
  • Failed GnomAD Quality Control
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -0.327
• 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]

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=0.0044184923).
• BP6: Variant 2-178658723-C-T is Benign according to our data. Variant chr2-178658723-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 192169.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.00182 (2573/1417624) while in subpopulation NFE AF = 0.00195 (2090/1074552). AF 95% confidence interval is 0.00188. There are 58 homozygotes in GnomAdExome4. There are 1252 alleles in the male GnomAdExome4 subpopulation. Median coverage is 28. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 58 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.37525G>A	p.Glu12509Lys	missense	Exon 183 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.34522+282G>A		intron	N/A	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.31741+282G>A		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.37525G>A	p.Glu12509Lys	missense	Exon 183 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.37525G>A	p.Glu12509Lys	missense	Exon 183 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.37249G>A	p.Glu12417Lys	missense	Exon 181 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.00123 AC: 173 AN: 140586 Hom.: 4 Cov.: 19

Gnomad AFR AF: 0.000287

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000371

Gnomad ASJ AF: 0.00880

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000253

Gnomad FIN AF: 0.000416

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00189

Gnomad OTH AF: 0.00105

GnomAD2 exomes AF: 0.00140 AC: 89 AN: 63646 AF XY: 0.00123

Gnomad AFR exome AF: 0.000179

Gnomad AMR exome AF: 0.00137

Gnomad ASJ exome AF: 0.00946

Gnomad EAS exome AF: 0.000126

Gnomad FIN exome AF: 0.000802

Gnomad NFE exome AF: 0.00213

Gnomad OTH exome AF: 0.000492

GnomAD4 exome AF: 0.00182 AC: 2573 AN: 1417624 Hom.: 58 Cov.: 28 AF XY: 0.00177 AC XY: 1252 AN XY: 706758

African (AFR) AF: 0.000153 AC: 5 AN: 32730

American (AMR) AF: 0.000792 AC: 35 AN: 44212

Ashkenazi Jewish (ASJ) AF: 0.00980 AC: 252 AN: 25710

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39478

South Asian (SAS) AF: 0.000399 AC: 34 AN: 85116

European-Finnish (FIN) AF: 0.000887 AC: 47 AN: 53016

Middle Eastern (MID) AF: 0.000246 AC: 1 AN: 4066

European-Non Finnish (NFE) AF: 0.00194 AC: 2090 AN: 1074552

Other (OTH) AF: 0.00184 AC: 108 AN: 58744

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00123 AC: 173 AN: 140666 Hom.: 4 Cov.: 19 AF XY: 0.00124 AC XY: 84 AN XY: 67882

African (AFR) AF: 0.000287 AC: 11 AN: 38392

American (AMR) AF: 0.000370 AC: 5 AN: 13496

Ashkenazi Jewish (ASJ) AF: 0.00880 AC: 29 AN: 3294

East Asian (EAS) AF: 0.00 AC: 0 AN: 4728

South Asian (SAS) AF: 0.000253 AC: 1 AN: 3948

European-Finnish (FIN) AF: 0.000416 AC: 4 AN: 9624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 280

European-Non Finnish (NFE) AF: 0.00189 AC: 121 AN: 64158

Other (OTH) AF: 0.00104 AC: 2 AN: 1918

Alfa AF: 0.000581 Hom.: 0

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	3	not specified (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	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	-0.43	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	17
DANN	Benign	0.77
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.62
FATHMM_MKL	Benign	0.076	N
LIST_S2	Benign	0.68	T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.0044	T
MetaSVM	Benign	-1.1	T
PhyloP100		-0.33
Mutation Taster		=90/10	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs201797790;

hg19: chr2-179523450;