rs72646847

Variant names:

• chr2-178589547-A-G
• rs72646847
• NM_001267550.2:c.62178T>C

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.62178T>C​(p.Thr20726Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00261 in 1,613,204 control chromosomes in the GnomAD database, including 115 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (62 hom., cov: 33)
  • Exomes 𝑓: 0.0014 (53 hom.)
• Consequence: TTN NM_001267550.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:23
• Conservation: PhyloP100: 0.135
• 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=-0.57).
• BP6: Variant 2-178589547-A-G is Benign according to our data. Variant chr2-178589547-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 47180.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.135 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0144 (2187/151984) while in subpopulation AFR AF = 0.0502 (2083/41498). AF 95% confidence interval is 0.0484. There are 62 homozygotes in GnomAd4. There are 1064 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 62 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	NM_001267550.2	MANE Select	c.62178T>C	p.Thr20726Thr	synonymous	Exon 304 of 363	NP_001254479.2
	TTN	NM_001256850.1		c.57255T>C	p.Thr19085Thr	synonymous	Exon 254 of 313	NP_001243779.1
	TTN	NM_133378.4		c.54474T>C	p.Thr18158Thr	synonymous	Exon 253 of 312	NP_596869.4

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	ENST00000589042.5	TSL:5 MANE Select	c.62178T>C	p.Thr20726Thr	synonymous	Exon 304 of 363	ENSP00000467141.1
	TTN	ENST00000446966.2	TSL:1	c.62022T>C	p.Thr20674Thr	synonymous	Exon 302 of 361	ENSP00000408004.2
	TTN	ENST00000436599.2	TSL:1	c.61902T>C	p.Thr20634Thr	synonymous	Exon 302 of 361	ENSP00000405517.2

Frequencies

GnomAD3 genomes AF: 0.0144 AC: 2183 AN: 151866 Hom.: 62 Cov.: 33

Gnomad AFR AF: 0.0503

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00499

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00321

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.00528

GnomAD2 exomes AF: 0.00346 AC: 858 AN: 247884 AF XY: 0.00268

Gnomad AFR exome AF: 0.0506

Gnomad AMR exome AF: 0.00166

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000714

Gnomad OTH exome AF: 0.00150

GnomAD4 exome AF: 0.00138 AC: 2018 AN: 1461220 Hom.: 53 Cov.: 33 AF XY: 0.00111 AC XY: 804 AN XY: 726882

African (AFR) AF: 0.0514 AC: 1718 AN: 33456

American (AMR) AF: 0.00217 AC: 97 AN: 44688

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26118

East Asian (EAS) AF: 0.00 AC: 0 AN: 39578

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86238

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53374

Middle Eastern (MID) AF: 0.00156 AC: 9 AN: 5758

European-Non Finnish (NFE) AF: 0.0000324 AC: 36 AN: 1111654

Other (OTH) AF: 0.00253 AC: 153 AN: 60356

GnomAD4 genome AF: 0.0144 AC: 2187 AN: 151984 Hom.: 62 Cov.: 33 AF XY: 0.0143 AC XY: 1064 AN XY: 74256

African (AFR) AF: 0.0502 AC: 2083 AN: 41498

American (AMR) AF: 0.00498 AC: 76 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5126

South Asian (SAS) AF: 0.000416 AC: 2 AN: 4808

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

Middle Eastern (MID) AF: 0.00345 AC: 1 AN: 290

European-Non Finnish (NFE) AF: 0.000206 AC: 14 AN: 67920

Other (OTH) AF: 0.00523 AC: 11 AN: 2104

Alfa AF: 0.00597 Hom.: 12

Bravo AF: 0.0161

Asia WGS AF: 0.00202 AC: 7 AN: 3476

EpiCase AF: 0.0000546

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	Cardiovascular phenotype (1)
-	-	1	Dilated cardiomyopathy 1G (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
CADD	Benign	0.82
DANN	Benign	0.73
PhyloP100		0.14
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: rs72646847; hg19: chr2-179454274;