rs55742743

Variant names:

• chr2-178537015-C-T
• rs55742743
• NM_001267550.2:c.100094G>A

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_001267550.2(TTN):​c.100094G>A​(p.Arg33365Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0186 in 1,613,248 control chromosomes in the GnomAD database, including 315 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R33365W) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.013 (19 hom., cov: 33)
  • Exomes 𝑓: 0.019 (296 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:25
• Conservation: PhyloP100: 7.91
• Publications: 20 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 -16 ACMG points.

• BP6: Variant 2-178537015-C-T is Benign according to our data. Variant chr2-178537015-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 47624.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 = 0.0126 (1920/152274) while in subpopulation NFE AF = 0.0211 (1432/68022). AF 95% confidence interval is 0.0201. There are 19 homozygotes in GnomAd4. There are 873 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 19 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.100094G>A	p.Arg33365Gln	missense	Exon 356 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.95171G>A	p.Arg31724Gln	missense	Exon 306 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.92390G>A	p.Arg30797Gln	missense	Exon 305 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.100094G>A	p.Arg33365Gln	missense	Exon 356 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.99938G>A	p.Arg33313Gln	missense	Exon 354 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.99818G>A	p.Arg33273Gln	missense	Exon 354 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.0126 AC: 1920 AN: 152156 Hom.: 19 Cov.: 33

Gnomad AFR AF: 0.00408

Gnomad AMI AF: 0.0175

Gnomad AMR AF: 0.00812

Gnomad ASJ AF: 0.0199

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00849

Gnomad FIN AF: 0.00405

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0210

Gnomad OTH AF: 0.0110

GnomAD2 exomes AF: 0.0125 AC: 3093 AN: 247674 AF XY: 0.0131

Gnomad AFR exome AF: 0.00306

Gnomad AMR exome AF: 0.00600

Gnomad ASJ exome AF: 0.0224

Gnomad EAS exome AF: 0.000112

Gnomad FIN exome AF: 0.00265

Gnomad NFE exome AF: 0.0202

Gnomad OTH exome AF: 0.0137

GnomAD4 exome AF: 0.0192 AC: 28017 AN: 1460974 Hom.: 296 Cov.: 33 AF XY: 0.0190 AC XY: 13773 AN XY: 726698

African (AFR) AF: 0.00332 AC: 111 AN: 33444

American (AMR) AF: 0.00676 AC: 302 AN: 44654

Ashkenazi Jewish (ASJ) AF: 0.0221 AC: 577 AN: 26110

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39650

South Asian (SAS) AF: 0.00763 AC: 657 AN: 86126

European-Finnish (FIN) AF: 0.00345 AC: 184 AN: 53354

Middle Eastern (MID) AF: 0.00642 AC: 37 AN: 5766

European-Non Finnish (NFE) AF: 0.0225 AC: 25046 AN: 1111528

Other (OTH) AF: 0.0183 AC: 1102 AN: 60342

GnomAD4 genome AF: 0.0126 AC: 1920 AN: 152274 Hom.: 19 Cov.: 33 AF XY: 0.0117 AC XY: 873 AN XY: 74444

African (AFR) AF: 0.00407 AC: 169 AN: 41556

American (AMR) AF: 0.00811 AC: 124 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0199 AC: 69 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00850 AC: 41 AN: 4824

European-Finnish (FIN) AF: 0.00405 AC: 43 AN: 10612

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0211 AC: 1432 AN: 68022

Other (OTH) AF: 0.0109 AC: 23 AN: 2114

Alfa AF: 0.0187 Hom.: 105

Bravo AF: 0.0134

TwinsUK AF: 0.0216 AC: 80

ALSPAC AF: 0.0239 AC: 92

ESP6500AA AF: 0.00522 AC: 20

ESP6500EA AF: 0.0210 AC: 173

ExAC AF: 0.0122 AC: 1472

Asia WGS AF: 0.00433 AC: 15 AN: 3478

EpiCase AF: 0.0199

EpiControl AF: 0.0209

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	10	not specified (10)
-	-	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	Cardiovascular phenotype (1)
-	-	1	Dilated cardiomyopathy 1G (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.17
CADD	Pathogenic	27
DANN	Uncertain	0.97
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D
MetaRNN	Benign	0.0082	T
MetaSVM	Uncertain	-0.12	T
MutationAssessor	Pathogenic	2.9	M
PhyloP100		7.9
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-3.1	D
REVEL	Uncertain	0.48
Sift	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.41
MPC		0.50
ClinPred		0.016	T
GERP RS		5.5
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.48		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.48		Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs55742743; hg19: chr2-179401742; COSMIC: COSV59917701; COSMIC: COSV59917701;