rs55801134

Variant names:

• chr2-178575436-C-G
• rs55801134
• NM_001267550.2:c.70696G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001267550.2(TTN):​c.70696G>C​(p.Gly23566Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0131 in 1,613,574 control chromosomes in the GnomAD database, including 207 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. G23566G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.012 (23 hom., cov: 32)
  • Exomes 𝑓: 0.013 (184 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:28
• Conservation: PhyloP100: 7.86
• Publications: 13 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007964224).
• BP6: Variant 2-178575436-C-G is Benign according to our data. Variant chr2-178575436-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 47290.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0116 (1760/152216) while in subpopulation NFE AF = 0.0142 (965/67990). AF 95% confidence interval is 0.0135. There are 23 homozygotes in GnomAd4. There are 945 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 23 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.70696G>C	p.Gly23566Arg	missense	Exon 326 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.65773G>C	p.Gly21925Arg	missense	Exon 276 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.62992G>C	p.Gly20998Arg	missense	Exon 275 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.70696G>C	p.Gly23566Arg	missense	Exon 326 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.70540G>C	p.Gly23514Arg	missense	Exon 324 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.70420G>C	p.Gly23474Arg	missense	Exon 324 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.0116 AC: 1761 AN: 152098 Hom.: 23 Cov.: 32

Gnomad AFR AF: 0.00244

Gnomad AMI AF: 0.00768

Gnomad AMR AF: 0.00550

Gnomad ASJ AF: 0.0112

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.0511

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0142

Gnomad OTH AF: 0.00623

GnomAD2 exomes AF: 0.0117 AC: 2892 AN: 248240 AF XY: 0.0114

Gnomad AFR exome AF: 0.00194

Gnomad AMR exome AF: 0.00296

Gnomad ASJ exome AF: 0.0123

Gnomad EAS exome AF: 0.0000559

Gnomad FIN exome AF: 0.0523

Gnomad NFE exome AF: 0.0124

Gnomad OTH exome AF: 0.00981

GnomAD4 exome AF: 0.0133 AC: 19395 AN: 1461358 Hom.: 184 Cov.: 36 AF XY: 0.0130 AC XY: 9434 AN XY: 726950

African (AFR) AF: 0.00179 AC: 60 AN: 33464

American (AMR) AF: 0.00295 AC: 132 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0109 AC: 284 AN: 26118

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39656

South Asian (SAS) AF: 0.00214 AC: 185 AN: 86248

European-Finnish (FIN) AF: 0.0478 AC: 2551 AN: 53394

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5762

European-Non Finnish (NFE) AF: 0.0139 AC: 15493 AN: 1111642

Other (OTH) AF: 0.0114 AC: 687 AN: 60352

GnomAD4 genome AF: 0.0116 AC: 1760 AN: 152216 Hom.: 23 Cov.: 32 AF XY: 0.0127 AC XY: 945 AN XY: 74400

African (AFR) AF: 0.00243 AC: 101 AN: 41560

American (AMR) AF: 0.00550 AC: 84 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.0112 AC: 39 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.00186 AC: 9 AN: 4830

European-Finnish (FIN) AF: 0.0511 AC: 542 AN: 10606

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

European-Non Finnish (NFE) AF: 0.0142 AC: 965 AN: 67990

Other (OTH) AF: 0.00616 AC: 13 AN: 2110

Alfa AF: 0.0120 Hom.: 16

Bravo AF: 0.00760

TwinsUK AF: 0.0121 AC: 45

ALSPAC AF: 0.0125 AC: 48

ESP6500AA AF: 0.00171 AC: 7

ESP6500EA AF: 0.0161 AC: 135

ExAC AF: 0.0106 AC: 1284

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.0109

EpiControl AF: 0.0104

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	11	not specified (11)
-	-	4	not provided (4)
-	-	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)
-	-	1	TTN-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.11
CADD	Benign	22
DANN	Benign	0.95
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D
MetaRNN	Benign	0.0080	T
MetaSVM	Uncertain	-0.24	T
MutationAssessor	Pathogenic	3.1	M
PhyloP100		7.9
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-5.6	D
REVEL	Uncertain	0.64
Sift	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.40
MPC		0.51
ClinPred		0.047	T
GERP RS		5.6
Mutation Taster		=93/7	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: rs55801134; hg19: chr2-179440163; COSMIC: COSV99045481; COSMIC: COSV99045481;