rs12474306

Variant names:

• chr2-178652292-A-T
• rs12474306
• NM_001267550.2:c.39183T>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001267550.2(TTN):​c.39183T>A​(p.Pro13061Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0103 in 1,613,714 control chromosomes in the GnomAD database, including 105 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0067 (0 hom., cov: 32)
  • Exomes 𝑓: 0.011 (105 hom.)
• Consequence: TTN NM_001267550.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:25
• Conservation: PhyloP100: -1.70
• Publications: 1 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.57).
• BP6: Variant 2-178652292-A-T is Benign according to our data. Variant chr2-178652292-A-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 46922.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.7 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00666 (1015/152292) while in subpopulation NFE AF = 0.0114 (776/68004). AF 95% confidence interval is 0.0107. There are 0 homozygotes in GnomAd4. There are 437 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 105 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.39183T>A	p.Pro13061Pro	synonymous	Exon 203 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.34662T>A	p.Pro11554Pro	synonymous	Exon 158 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.31881T>A	p.Pro10627Pro	synonymous	Exon 157 of 312	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.39183T>A	p.Pro13061Pro	synonymous	Exon 203 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.39183T>A	p.Pro13061Pro	synonymous	Exon 203 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.38907T>A	p.Pro12969Pro	synonymous	Exon 201 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.00668 AC: 1017 AN: 152174 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00253

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.00399

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.00376

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0114

Gnomad OTH AF: 0.00478

GnomAD2 exomes AF: 0.00771 AC: 1922 AN: 249144 AF XY: 0.00759

Gnomad AFR exome AF: 0.00174

Gnomad AMR exome AF: 0.00863

Gnomad ASJ exome AF: 0.00199

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00487

Gnomad NFE exome AF: 0.0120

Gnomad OTH exome AF: 0.00480

GnomAD4 exome AF: 0.0107 AC: 15666 AN: 1461422 Hom.: 105 Cov.: 33 AF XY: 0.0104 AC XY: 7568 AN XY: 726988

African (AFR) AF: 0.00152 AC: 51 AN: 33464

American (AMR) AF: 0.00807 AC: 361 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00176 AC: 46 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00297 AC: 256 AN: 86242

European-Finnish (FIN) AF: 0.00592 AC: 316 AN: 53400

Middle Eastern (MID) AF: 0.00122 AC: 7 AN: 5726

European-Non Finnish (NFE) AF: 0.0128 AC: 14186 AN: 1111702

Other (OTH) AF: 0.00734 AC: 443 AN: 60352

GnomAD4 genome AF: 0.00666 AC: 1015 AN: 152292 Hom.: 0 Cov.: 32 AF XY: 0.00587 AC XY: 437 AN XY: 74452

African (AFR) AF: 0.00253 AC: 105 AN: 41582

American (AMR) AF: 0.00392 AC: 60 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00288 AC: 10 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5170

South Asian (SAS) AF: 0.00166 AC: 8 AN: 4824

European-Finnish (FIN) AF: 0.00376 AC: 40 AN: 10626

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

European-Non Finnish (NFE) AF: 0.0114 AC: 776 AN: 68004

Other (OTH) AF: 0.00473 AC: 10 AN: 2116

Alfa AF: 0.00904 Hom.: 4

Bravo AF: 0.00706

EpiCase AF: 0.00966

EpiControl AF: 0.00931

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	9	not specified (9)
-	-	5	not provided (5)
-	-	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	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	-0.57
CADD	Benign	2.0
DANN	Benign	0.80
PhyloP100		-1.7
Mutation Taster		=88/12	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: rs12474306; hg19: chr2-179517019;