rs55762754

Variant names:

• chr2-178572307-C-G
• rs55762754
• NM_001267550.2:c.73825G>C

Your query was ambiguous. Multiple possible variants found:

• chr2-178572307-C-G
• chr2-178572307-C-T

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.73825G>C​(p.Glu24609Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00294 in 1,611,664 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. E24609E) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0030 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0029 (12 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:3 B:20
• Conservation: PhyloP100: 7.86
• Publications: 8 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=0.007963955).
• BP6: Variant 2-178572307-C-G is Benign according to our data. Variant chr2-178572307-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 47322.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00302 (460/152228) while in subpopulation NFE AF = 0.00413 (281/67994). AF 95% confidence interval is 0.00374. There are 2 homozygotes in GnomAd4. There are 248 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 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.73825G>C	p.Glu24609Gln	missense	Exon 326 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.68902G>C	p.Glu22968Gln	missense	Exon 276 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.66121G>C	p.Glu22041Gln	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.73825G>C	p.Glu24609Gln	missense	Exon 326 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.73669G>C	p.Glu24557Gln	missense	Exon 324 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.73549G>C	p.Glu24517Gln	missense	Exon 324 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.00302 AC: 460 AN: 152110 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000531

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.000786

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.0123

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00413

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00315 AC: 782 AN: 247928 AF XY: 0.00318

Gnomad AFR exome AF: 0.000323

Gnomad AMR exome AF: 0.00125

Gnomad ASJ exome AF: 0.000599

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0129

Gnomad NFE exome AF: 0.00373

Gnomad OTH exome AF: 0.00399

GnomAD4 exome AF: 0.00294 AC: 4286 AN: 1459436 Hom.: 12 Cov.: 38 AF XY: 0.00293 AC XY: 2126 AN XY: 725572

African (AFR) AF: 0.000269 AC: 9 AN: 33430

American (AMR) AF: 0.00123 AC: 55 AN: 44672

Ashkenazi Jewish (ASJ) AF: 0.000575 AC: 15 AN: 26104

East Asian (EAS) AF: 0.00 AC: 0 AN: 39552

South Asian (SAS) AF: 0.000371 AC: 32 AN: 86202

European-Finnish (FIN) AF: 0.0134 AC: 715 AN: 53358

Middle Eastern (MID) AF: 0.000870 AC: 5 AN: 5750

European-Non Finnish (NFE) AF: 0.00296 AC: 3287 AN: 1110102

Other (OTH) AF: 0.00279 AC: 168 AN: 60266

GnomAD4 genome AF: 0.00302 AC: 460 AN: 152228 Hom.: 2 Cov.: 32 AF XY: 0.00333 AC XY: 248 AN XY: 74410

African (AFR) AF: 0.000529 AC: 22 AN: 41566

American (AMR) AF: 0.000785 AC: 12 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.000865 AC: 3 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5154

South Asian (SAS) AF: 0.000829 AC: 4 AN: 4824

European-Finnish (FIN) AF: 0.0123 AC: 131 AN: 10622

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

European-Non Finnish (NFE) AF: 0.00413 AC: 281 AN: 67994

Other (OTH) AF: 0.00284 AC: 6 AN: 2112

Alfa AF: 0.00314 Hom.: 2

Bravo AF: 0.00201

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.000259 AC: 1

ESP6500EA AF: 0.00241 AC: 20

ExAC AF: 0.00316 AC: 382

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00333

EpiControl AF: 0.00303

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	11	not specified (11)
-	-	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	-	-	Tip-toe gait (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	20
DANN	Benign	0.85
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D
MetaRNN	Benign	0.0080	T
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	1.9	M
PhyloP100		7.9
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.21
Sift	Benign	0.087	T
Polyphen		0.85	P
Vest4		0.24
MVP		0.36
MPC		0.12
ClinPred		0.043	T
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=95/5	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: rs55762754; hg19: chr2-179437034;