rs72648904

Variant names:

• chr2-178748924-G-A
• rs72648904
• NM_001267550.2:c.11311+4200C>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_133379.5(TTN):​c.13476C>T​(p.Asp4492Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0314 in 1,612,396 control chromosomes in the GnomAD database, including 967 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.023 (48 hom., cov: 32)
  • Exomes 𝑓: 0.032 (919 hom.)
• Consequence: TTN NM_133379.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.757
• Publications: 4 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=-0.82).
• BP6: Variant 2-178748924-G-A is Benign according to our data. Variant chr2-178748924-G-A is described in ClinVar as Benign. ClinVar VariationId is 47756.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.757 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0229 (3475/152040) while in subpopulation NFE AF = 0.0337 (2287/67904). AF 95% confidence interval is 0.0325. There are 48 homozygotes in GnomAd4. There are 1710 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 48 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_133379.5. 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.11311+4200C>T		intron	N/A	NP_001254479.2	Q8WZ42-12
	TTN	NM_133379.5		c.13476C>T	p.Asp4492Asp	synonymous	Exon 46 of 46	NP_596870.2	Q8WZ42-6
	TTN	NM_001256850.1		c.10360+4200C>T		intron	N/A	NP_001243779.1	Q8WZ42-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	ENST00000589042.5	TSL:5 MANE Select	c.11311+4200C>T		intron	N/A	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.11311+4200C>T		intron	N/A	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.11035+4200C>T		intron	N/A	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.0229 AC: 3477 AN: 151922 Hom.: 48 Cov.: 32

Gnomad AFR AF: 0.00708

Gnomad AMI AF: 0.00768

Gnomad AMR AF: 0.0206

Gnomad ASJ AF: 0.00865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0124

Gnomad FIN AF: 0.0386

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0337

Gnomad OTH AF: 0.0331

GnomAD2 exomes AF: 0.0228 AC: 5703 AN: 250186 AF XY: 0.0235

Gnomad AFR exome AF: 0.00678

Gnomad AMR exome AF: 0.0159

Gnomad ASJ exome AF: 0.00815

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.0361

Gnomad NFE exome AF: 0.0327

Gnomad OTH exome AF: 0.0285

GnomAD4 exome AF: 0.0323 AC: 47196 AN: 1460356 Hom.: 919 Cov.: 35 AF XY: 0.0316 AC XY: 22956 AN XY: 726492

African (AFR) AF: 0.00518 AC: 173 AN: 33412

American (AMR) AF: 0.0170 AC: 759 AN: 44592

Ashkenazi Jewish (ASJ) AF: 0.00878 AC: 229 AN: 26076

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39608

South Asian (SAS) AF: 0.0107 AC: 925 AN: 86190

European-Finnish (FIN) AF: 0.0325 AC: 1727 AN: 53100

Middle Eastern (MID) AF: 0.0165 AC: 95 AN: 5752

European-Non Finnish (NFE) AF: 0.0374 AC: 41553 AN: 1111316

Other (OTH) AF: 0.0287 AC: 1731 AN: 60310

GnomAD4 genome AF: 0.0229 AC: 3475 AN: 152040 Hom.: 48 Cov.: 32 AF XY: 0.0230 AC XY: 1710 AN XY: 74340

African (AFR) AF: 0.00703 AC: 292 AN: 41532

American (AMR) AF: 0.0206 AC: 314 AN: 15240

Ashkenazi Jewish (ASJ) AF: 0.00865 AC: 30 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5160

South Asian (SAS) AF: 0.0124 AC: 60 AN: 4824

European-Finnish (FIN) AF: 0.0386 AC: 409 AN: 10602

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.0337 AC: 2287 AN: 67904

Other (OTH) AF: 0.0323 AC: 68 AN: 2104

Alfa AF: 0.0277 Hom.: 32

Bravo AF: 0.0217

Asia WGS AF: 0.00289 AC: 10 AN: 3476

EpiCase AF: 0.0343

EpiControl AF: 0.0333

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	4	not provided (4)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.79
DANN	Benign	0.42
PhyloP100		-0.76
Mutation Taster		=98/2	polymorphism (auto)

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: rs72648904; hg19: chr2-179613651;