2-178591876-G-T

Variant names:

• chr2-178591876-G-T
• rs202017608
• NM_001267550.2:c.59943C>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.59943C>A​(p.Pro19981Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00116 in 1,610,950 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P19981P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00078 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (20 hom.)
• Consequence: TTN NM_001267550.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:23
• Conservation: PhyloP100: -0.0570
• 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=-0.55).
• BP6: Variant 2-178591876-G-T is Benign according to our data. Variant chr2-178591876-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 47156.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.057 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000775 (118/152170) while in subpopulation SAS AF = 0.00996 (48/4818). AF 95% confidence interval is 0.00772. There are 1 homozygotes in GnomAd4. There are 65 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 20 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.59943C>A	p.Pro19981Pro	synonymous	Exon 303 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.55020C>A	p.Pro18340Pro	synonymous	Exon 253 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.52239C>A	p.Pro17413Pro	synonymous	Exon 252 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.59943C>A	p.Pro19981Pro	synonymous	Exon 303 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.59787C>A	p.Pro19929Pro	synonymous	Exon 301 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.59667C>A	p.Pro19889Pro	synonymous	Exon 301 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.000769 AC: 117 AN: 152052 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000656

Gnomad ASJ AF: 0.0101

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.00975

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.00244 AC: 598 AN: 245216 AF XY: 0.00306

Gnomad AFR exome AF: 0.000130

Gnomad AMR exome AF: 0.00101

Gnomad ASJ exome AF: 0.0106

Gnomad EAS exome AF: 0.0000566

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000512

Gnomad OTH exome AF: 0.00303

GnomAD4 exome AF: 0.00120 AC: 1755 AN: 1458780 Hom.: 20 Cov.: 35 AF XY: 0.00159 AC XY: 1157 AN XY: 725546

African (AFR) AF: 0.000211 AC: 7 AN: 33154

American (AMR) AF: 0.000861 AC: 38 AN: 44124

Ashkenazi Jewish (ASJ) AF: 0.0103 AC: 269 AN: 26072

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39546

South Asian (SAS) AF: 0.0121 AC: 1031 AN: 85470

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53378

Middle Eastern (MID) AF: 0.00661 AC: 38 AN: 5746

European-Non Finnish (NFE) AF: 0.000230 AC: 256 AN: 1111046

Other (OTH) AF: 0.00191 AC: 115 AN: 60244

GnomAD4 genome AF: 0.000775 AC: 118 AN: 152170 Hom.: 1 Cov.: 32 AF XY: 0.000874 AC XY: 65 AN XY: 74366

African (AFR) AF: 0.0000241 AC: 1 AN: 41572

American (AMR) AF: 0.000655 AC: 10 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.0101 AC: 35 AN: 3468

East Asian (EAS) AF: 0.000195 AC: 1 AN: 5136

South Asian (SAS) AF: 0.00996 AC: 48 AN: 4818

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

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000265 AC: 18 AN: 67964

Other (OTH) AF: 0.00142 AC: 3 AN: 2112

Alfa AF: 0.00113 Hom.: 1

Bravo AF: 0.000665

Asia WGS AF: 0.00318 AC: 11 AN: 3478

EpiCase AF: 0.000655

EpiControl AF: 0.000890

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	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	-0.55
CADD	Benign	0.44
DANN	Benign	0.78
PhyloP100		-0.057
Mutation Taster		=77/23	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs202017608; hg19: chr2-179456603;