rs146163169

Variant names:

• chr2-178613912-T-A
• rs146163169
• NM_001267550.2:c.49371A>T

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.49371A>T​(p.Leu16457Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00219 in 1,608,822 control chromosomes in the GnomAD database, including 53 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0018 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0022 (48 hom.)
• Consequence: TTN NM_001267550.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:25
• Conservation: PhyloP100: -1.01
• 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]

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant 2-178613912-T-A is Benign according to our data. Variant chr2-178613912-T-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 47028.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.01 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00181 (275/152092) while in subpopulation SAS AF = 0.0243 (117/4824). AF 95% confidence interval is 0.0207. There are 5 homozygotes in GnomAd4. There are 155 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 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.49371A>T	p.Leu16457Leu	synonymous	Exon 263 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.44448A>T	p.Leu14816Leu	synonymous	Exon 213 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.41667A>T	p.Leu13889Leu	synonymous	Exon 212 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.49371A>T	p.Leu16457Leu	synonymous	Exon 263 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.49215A>T	p.Leu16405Leu	synonymous	Exon 261 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.49095A>T	p.Leu16365Leu	synonymous	Exon 261 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.00179 AC: 272 AN: 151974 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00184

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0236

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00166

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00372 AC: 911 AN: 244752 AF XY: 0.00479

Gnomad AFR exome AF: 0.000195

Gnomad AMR exome AF: 0.000710

Gnomad ASJ exome AF: 0.000918

Gnomad EAS exome AF: 0.0000563

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00180

Gnomad OTH exome AF: 0.00354

GnomAD4 exome AF: 0.00223 AC: 3248 AN: 1456730 Hom.: 48 Cov.: 32 AF XY: 0.00285 AC XY: 2064 AN XY: 724216

African (AFR) AF: 0.000422 AC: 14 AN: 33208

American (AMR) AF: 0.000634 AC: 28 AN: 44156

Ashkenazi Jewish (ASJ) AF: 0.000849 AC: 22 AN: 25900

East Asian (EAS) AF: 0.000177 AC: 7 AN: 39576

South Asian (SAS) AF: 0.0211 AC: 1803 AN: 85422

European-Finnish (FIN) AF: 0.0000751 AC: 4 AN: 53266

Middle Eastern (MID) AF: 0.00436 AC: 25 AN: 5730

European-Non Finnish (NFE) AF: 0.00105 AC: 1166 AN: 1109358

Other (OTH) AF: 0.00298 AC: 179 AN: 60114

GnomAD4 genome AF: 0.00181 AC: 275 AN: 152092 Hom.: 5 Cov.: 32 AF XY: 0.00208 AC XY: 155 AN XY: 74350

African (AFR) AF: 0.000241 AC: 10 AN: 41552

American (AMR) AF: 0.00184 AC: 28 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.000865 AC: 3 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5120

South Asian (SAS) AF: 0.0243 AC: 117 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

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

European-Non Finnish (NFE) AF: 0.00166 AC: 113 AN: 67928

Other (OTH) AF: 0.00189 AC: 4 AN: 2114

Alfa AF: 0.00132 Hom.: 0

Bravo AF: 0.00105

Asia WGS AF: 0.0130 AC: 44 AN: 3476

EpiCase AF: 0.00273

EpiControl AF: 0.00268

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	-	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	Cardiovascular phenotype (1)
-	-	1	Dilated cardiomyopathy 1G (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	0.13
DANN	Benign	0.72
PhyloP100		-1.0
Mutation Taster		=95/5	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: rs146163169; hg19: chr2-179478639;