rs72650077

Variant names:

• chr2-178636624-G-A
• rs72650077
• NM_001267550.2:c.41103C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Moderate BP6 BP7 BS1 BS2

The NM_001267550.2(TTN):​c.41103C>T​(p.Gly13701Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00318 in 1,613,398 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0024 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0033 (11 hom.)
• Consequence: TTN NM_001267550.2 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:20
• Conservation: PhyloP100: 0.537
• 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.39).
• BP6: Variant 2-178636624-G-A is Benign according to our data. Variant chr2-178636624-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 46943.
• BP7: Synonymous conserved (PhyloP=0.537 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00244 (371/152176) while in subpopulation NFE AF = 0.00393 (267/67976). AF 95% confidence interval is 0.00354. There are 0 homozygotes in GnomAd4. There are 158 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 11 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.41103C>T	p.Gly13701Gly	synonymous	Exon 225 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.36180C>T	p.Gly12060Gly	synonymous	Exon 175 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.33399C>T	p.Gly11133Gly	synonymous	Exon 174 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.41103C>T	p.Gly13701Gly	synonymous	Exon 225 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.40947C>T	p.Gly13649Gly	synonymous	Exon 223 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.40827C>T	p.Gly13609Gly	synonymous	Exon 223 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.00244 AC: 371 AN: 152058 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000362

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00282

Gnomad ASJ AF: 0.00403

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00188

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00393

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00294 AC: 729 AN: 248360 AF XY: 0.00289

Gnomad AFR exome AF: 0.000258

Gnomad AMR exome AF: 0.00299

Gnomad ASJ exome AF: 0.00309

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00265

Gnomad NFE exome AF: 0.00428

Gnomad OTH exome AF: 0.00532

GnomAD4 exome AF: 0.00326 AC: 4757 AN: 1461222 Hom.: 11 Cov.: 32 AF XY: 0.00322 AC XY: 2341 AN XY: 726890

African (AFR) AF: 0.000389 AC: 13 AN: 33454

American (AMR) AF: 0.00286 AC: 128 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00345 AC: 90 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39602

South Asian (SAS) AF: 0.000777 AC: 67 AN: 86248

European-Finnish (FIN) AF: 0.00294 AC: 157 AN: 53388

Middle Eastern (MID) AF: 0.00538 AC: 31 AN: 5762

European-Non Finnish (NFE) AF: 0.00367 AC: 4075 AN: 1111598

Other (OTH) AF: 0.00325 AC: 196 AN: 60340

GnomAD4 genome AF: 0.00244 AC: 371 AN: 152176 Hom.: 0 Cov.: 32 AF XY: 0.00212 AC XY: 158 AN XY: 74368

African (AFR) AF: 0.000361 AC: 15 AN: 41554

American (AMR) AF: 0.00282 AC: 43 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00403 AC: 14 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5142

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4822

European-Finnish (FIN) AF: 0.00188 AC: 20 AN: 10622

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

European-Non Finnish (NFE) AF: 0.00393 AC: 267 AN: 67976

Other (OTH) AF: 0.00332 AC: 7 AN: 2110

Alfa AF: 0.00361 Hom.: 2

Bravo AF: 0.00270

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00458

EpiControl AF: 0.00445

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	12	not specified (12)
-	-	3	not provided (3)
-	1	-	Autosomal recessive limb-girdle muscular dystrophy type 2J (1)
-	-	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)
-	1	-	Early-onset myopathy with fatal cardiomyopathy (1)
-	-	1	Myopathy, myofibrillar, 9, with early respiratory failure (1)
-	-	1	Tibial muscular dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.39
CADD	Benign	3.4
DANN	Benign	0.80
PhyloP100		0.54
Mutation Taster		=82/18	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: rs72650077; hg19: chr2-179501351;