rs1453109927

Variant names:

• chr3-134603757-C-T
• rs1453109927
• NM_178554.6:c.1808G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_178554.6(KY):​c.1808G>A​(p.Gly603Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000822 in 1,459,974 control chromosomes in the GnomAD database, with no homozygous occurrence. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: KY NM_178554.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.58
• Publications: 0 publications found

Genes affected

KY (HGNC:26576): (kyphoscoliosis peptidase) The protein encoded by this gene belongs to the transglutaminase-like superfamily. The protein is involved in the function, maturation and stabilization of the neuromuscular junction and may be required for normal muscle growth. Mutations in this gene are associated with myopathy, myofibrillar, 7. [provided by RefSeq, Apr 2017]

ENSG00000288700 (HGNC:):

CEP63 (HGNC:25815): (centrosomal protein 63) This gene encodes a protein with six coiled-coil domains. The protein is localized to the centrosome, a non-membraneous organelle that functions as the major microtubule-organizing center in animal cells. Several alternatively spliced transcript variants have been found, but their biological validity has not been determined. [provided by RefSeq, Jul 2008]

CEP63 Gene-Disease associations (from GenCC):

• Seckel syndrome 6

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• autosomal recessive primary microcephaly

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_178554.6. 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
	KY	NM_178554.6	MANE Select	c.1808G>A	p.Gly603Asp	missense	Exon 11 of 11	NP_848649.3
	KY	NM_001350859.2		c.1760G>A	p.Gly587Asp	missense	Exon 10 of 10	NP_001337788.1
	KY	NM_001366276.1		c.1745G>A	p.Gly582Asp	missense	Exon 10 of 10	NP_001353205.1	Q8NBH2-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KY	ENST00000423778.7	TSL:5 MANE Select	c.1808G>A	p.Gly603Asp	missense	Exon 11 of 11	ENSP00000397598.2	Q8NBH2-4
	KY	ENST00000503669.1	TSL:1	c.*690G>A		3_prime_UTR	Exon 10 of 10	ENSP00000426777.1	B4DGA7
	KY	ENST00000864999.1		c.1754G>A	p.Gly585Asp	missense	Exon 11 of 11	ENSP00000535058.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000403 AC: 1 AN: 248314 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000888

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000822 AC: 12 AN: 1459974 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 725982

African (AFR) AF: 0.00 AC: 0 AN: 33450

American (AMR) AF: 0.00 AC: 0 AN: 44592

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26060

East Asian (EAS) AF: 0.00 AC: 0 AN: 39640

South Asian (SAS) AF: 0.00 AC: 0 AN: 86102

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53366

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.0000108 AC: 12 AN: 1110710

Other (OTH) AF: 0.00 AC: 0 AN: 60298

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000469 Hom.: 0

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.0067	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	21
DANN	Uncertain	0.99
Eigen	Benign	0.18
Eigen_PC	Uncertain	0.22
FATHMM_MKL	Benign	0.54	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.040	D
MetaRNN	Uncertain	0.48	T
MetaSVM	Benign	-1.1	T
PhyloP100		3.6
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.19
Sift	Benign	0.20	T
Sift4G	Benign	0.17	T
Polyphen		0.87	P
Vest4		0.58
MutPred		0.52		Loss of sheet (P = 0.0037)
MVP		0.53
MPC		0.36
ClinPred		0.36	T
GERP RS		5.8
gMVP		0.57
Mutation Taster		=87/13	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: rs1453109927; hg19: chr3-134322599;