rs147524531

Variant names:

• chr2-178702461-G-A
• rs147524531
• NM_001267550.2:c.30426C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_001267550.2(TTN):​c.30426C>T​(p.Asp10142Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000521 in 1,613,740 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0028 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00028 (5 hom.)
• Consequence: TTN NM_001267550.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:23
• Conservation: PhyloP100: -0.237
• 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]

LOC124906100 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.44).
• BP6: Variant 2-178702461-G-A is Benign according to our data. Variant chr2-178702461-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 46834.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.237 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00282 (429/152122) while in subpopulation AFR AF = 0.00981 (407/41494). AF 95% confidence interval is 0.00902. There are 1 homozygotes in GnomAd4. There are 192 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 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.30426C>T	p.Asp10142Asp	synonymous	Exon 107 of 363	NP_001254479.2
	TTN	NM_001256850.1		c.29475C>T	p.Asp9825Asp	synonymous	Exon 105 of 313	NP_001243779.1
	TTN	NM_133378.4		c.26694C>T	p.Asp8898Asp	synonymous	Exon 104 of 312	NP_596869.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	ENST00000589042.5	TSL:5 MANE Select	c.30426C>T	p.Asp10142Asp	synonymous	Exon 107 of 363	ENSP00000467141.1
	TTN	ENST00000446966.2	TSL:1	c.30426C>T	p.Asp10142Asp	synonymous	Exon 107 of 361	ENSP00000408004.2
	TTN	ENST00000436599.2	TSL:1	c.30150C>T	p.Asp10050Asp	synonymous	Exon 105 of 361	ENSP00000405517.2

Frequencies

GnomAD3 genomes AF: 0.00282 AC: 428 AN: 152004 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00981

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000852

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00336

GnomAD2 exomes AF: 0.000791 AC: 197 AN: 249180 AF XY: 0.000510

Gnomad AFR exome AF: 0.0112

Gnomad AMR exome AF: 0.000464

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000556

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000266

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.000282 AC: 412 AN: 1461618 Hom.: 5 Cov.: 32 AF XY: 0.000241 AC XY: 175 AN XY: 727092

African (AFR) AF: 0.00956 AC: 320 AN: 33476

American (AMR) AF: 0.000492 AC: 22 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39698

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53396

Middle Eastern (MID) AF: 0.000349 AC: 2 AN: 5726

European-Non Finnish (NFE) AF: 0.0000108 AC: 12 AN: 1111856

Other (OTH) AF: 0.000779 AC: 47 AN: 60370

GnomAD4 genome AF: 0.00282 AC: 429 AN: 152122 Hom.: 1 Cov.: 32 AF XY: 0.00258 AC XY: 192 AN XY: 74364

African (AFR) AF: 0.00981 AC: 407 AN: 41494

American (AMR) AF: 0.000851 AC: 13 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10574

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67992

Other (OTH) AF: 0.00332 AC: 7 AN: 2106

Alfa AF: 0.00162 Hom.: 2

Bravo AF: 0.00303

Asia WGS AF: 0.00404 AC: 14 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	-	3	not provided (3)
-	-	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)
-	-	1	TTN-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.44
CADD	Benign	1.5
DANN	Benign	0.82
PhyloP100		-0.24
PromoterAI		-0.0048	Neutral
Mutation Taster		=89/11	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: rs147524531; hg19: chr2-179567188;