rs141973925

Variant names:

• chr2-178590625-C-T
• rs141973925
• NM_001267550.2:c.61100G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001267550.2(TTN):​c.61100G>A​(p.Arg20367Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00451 in 1,612,888 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R20367W) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0029 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0047 (17 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:23
• Conservation: PhyloP100: 6.06
• Publications: 15 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008304775).
• BP6: Variant 2-178590625-C-T is Benign according to our data. Variant chr2-178590625-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 47168.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00291 (443/152072) while in subpopulation NFE AF = 0.00521 (354/67958). AF 95% confidence interval is 0.00476. There are 0 homozygotes in GnomAd4. There are 189 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 17 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.61100G>A	p.Arg20367Gln	missense	Exon 304 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.56177G>A	p.Arg18726Gln	missense	Exon 254 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.53396G>A	p.Arg17799Gln	missense	Exon 253 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.61100G>A	p.Arg20367Gln	missense	Exon 304 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.60944G>A	p.Arg20315Gln	missense	Exon 302 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.60824G>A	p.Arg20275Gln	missense	Exon 302 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.00292 AC: 443 AN: 151954 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000676

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00223

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00170

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00521

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00347 AC: 861 AN: 248222 AF XY: 0.00339

Gnomad AFR exome AF: 0.000905

Gnomad AMR exome AF: 0.00122

Gnomad ASJ exome AF: 0.00110

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00205

Gnomad NFE exome AF: 0.00636

Gnomad OTH exome AF: 0.00332

GnomAD4 exome AF: 0.00468 AC: 6831 AN: 1460816 Hom.: 17 Cov.: 35 AF XY: 0.00452 AC XY: 3286 AN XY: 726676

African (AFR) AF: 0.000957 AC: 32 AN: 33428

American (AMR) AF: 0.00152 AC: 68 AN: 44676

Ashkenazi Jewish (ASJ) AF: 0.000843 AC: 22 AN: 26092

East Asian (EAS) AF: 0.00 AC: 0 AN: 39624

South Asian (SAS) AF: 0.000348 AC: 30 AN: 86160

European-Finnish (FIN) AF: 0.00187 AC: 100 AN: 53364

Middle Eastern (MID) AF: 0.00191 AC: 11 AN: 5746

European-Non Finnish (NFE) AF: 0.00570 AC: 6335 AN: 1111384

Other (OTH) AF: 0.00386 AC: 233 AN: 60342

GnomAD4 genome AF: 0.00291 AC: 443 AN: 152072 Hom.: 0 Cov.: 33 AF XY: 0.00254 AC XY: 189 AN XY: 74312

African (AFR) AF: 0.000674 AC: 28 AN: 41524

American (AMR) AF: 0.00223 AC: 34 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5136

South Asian (SAS) AF: 0.00 AC: 0 AN: 4808

European-Finnish (FIN) AF: 0.00170 AC: 18 AN: 10584

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

European-Non Finnish (NFE) AF: 0.00521 AC: 354 AN: 67958

Other (OTH) AF: 0.00237 AC: 5 AN: 2114

Alfa AF: 0.00440 Hom.: 5

Bravo AF: 0.00310

TwinsUK AF: 0.00512 AC: 19

ALSPAC AF: 0.00337 AC: 13

ESP6500AA AF: 0.00133 AC: 5

ESP6500EA AF: 0.00425 AC: 35

ExAC AF: 0.00381 AC: 461

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00481

EpiControl AF: 0.00547

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	12	not specified (12)
-	-	4	not provided (4)
-	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)
-	-	1	TTN-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	23
DANN	Benign	0.97
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.0098	T
MetaRNN	Benign	0.0083	T
MetaSVM	Benign	-0.75	T
MutationAssessor	Benign	2.0	M
PhyloP100		6.1
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-2.9	D
REVEL	Uncertain	0.31
Sift	Uncertain	0.017	D
Polyphen		1.0	D
Vest4		0.42
MVP		0.19
MPC		0.49
ClinPred		0.015	T
GERP RS		6.1
Mutation Taster		=99/1	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: rs141973925; hg19: chr2-179455352;