2-65071746-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_015147.3(CEP68):c.650G>A(p.Arg217His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000594 in 1,613,686 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.00066 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00059 (12 hom.)
• Consequence: CEP68 NM_015147.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.185

Genes affected

CEP68 (HGNC:29076): (centrosomal protein 68) Enables protein domain specific binding activity and protein kinase binding activity. Involved in centriole-centriole cohesion and protein localization to organelle. Located in several cellular components, including centriolar satellite; cytosol; and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

RAB1A (HGNC:9758): (RAB1A, member RAS oncogene family) This gene encodes a member of the Ras superfamily of GTPases. Members of the gene family cycle between inactive GDP-bound and active GTP-bound forms. This small GTPase controls vesicle traffic from the endoplasmic reticulum to the Golgi apparatus. Multiple alternatively spliced transcript variants have been identified for this gene which encode different protein isoforms. [provided by RefSeq, Oct 2008]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002495855).
• BP6: Variant 2-65071746-G-A is Benign according to our data. Variant chr2-65071746-G-A is described in ClinVar as [Benign]. Clinvar id is 781681.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.000586 (857/1461422) while in subpopulation AMR AF= 0.0172 (771/44716). AF 95% confidence interval is 0.0162. There are 12 homozygotes in gnomad4_exome. There are 386 alleles in male gnomad4_exome subpopulation. Median coverage is 34. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CEP68	NM_015147.3	c.650G>A	p.Arg217His	missense_variant	3/7	ENST00000377990.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CEP68	ENST00000377990.7	c.650G>A	p.Arg217His	missense_variant	3/7	1	NM_015147.3	P2

Frequencies

GnomAD3 genomes AF: 0.000664 AC: 101 AN: 152146 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00616

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00264 AC: 662 AN: 250696 Hom.: 10 AF XY: 0.00211 AC XY: 286 AN XY: 135526

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.0177

Gnomad ASJ exome AF: 0.0000995

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000882

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000265

Gnomad OTH exome AF: 0.00294

GnomAD4 exome AF: 0.000586 AC: 857 AN: 1461422 Hom.: 12 Cov.: 34 AF XY: 0.000531 AC XY: 386 AN XY: 726974

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.0172

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000510

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000810

Gnomad4 OTH exome AF: 0.000480

GnomAD4 genome AF: 0.000663 AC: 101 AN: 152264 Hom.: 0 Cov.: 31 AF XY: 0.000658 AC XY: 49 AN XY: 74450

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.00615

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000181 Hom.: 0

Bravo AF: 0.00154

ExAC AF: 0.00207 AC: 251

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jun 06, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.77
Cadd	Benign	5.6
Dann	Benign	0.91
DEOGEN2	Benign	0.0050	T;.
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.027	N
LIST_S2	Benign	0.63	T;T
MetaRNN	Benign	0.0025	T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.0	L;L
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.19	T
PROVEAN	Benign	-1.4	N;N
REVEL	Benign	0.022
Sift	Benign	0.057	T;T
Sift4G	Benign	0.13	T;T
Polyphen		0.0020	B;B
Vest4		0.040
MVP		0.055
MPC		0.053
ClinPred		0.010	T
GERP RS		-4.8
Varity_R		0.031
gMVP		0.12

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

Publications

LitVar

Other links and lift over

dbSNP: rs183284304; hg19: chr2-65298880;