2-65072196-T-A

Position:

• chr2-65072196-T-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_015147.3(CEP68):​c.1100T>A​(p.Phe367Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0139 in 1,614,036 control chromosomes in the GnomAD database, including 190 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (12 hom., cov: 32)
  • Exomes 𝑓: 0.014 (178 hom.)
• Consequence: CEP68 NM_015147.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.597

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004357666).
• BP6: Variant 2-65072196-T-A is Benign according to our data. Variant chr2-65072196-T-A is described in ClinVar as [Benign]. Clinvar id is 788725.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 = 0.0108 (1641/152158) while in subpopulation NFE AF= 0.0171 (1162/67968). AF 95% confidence interval is 0.0163. There are 12 homozygotes in gnomad4. There are 731 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 12 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CEP68	NM_015147.3	c.1100T>A	p.Phe367Tyr	missense_variant	3/7	ENST00000377990.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CEP68	ENST00000377990.7	c.1100T>A	p.Phe367Tyr	missense_variant	3/7	1	NM_015147.3	P2

Frequencies

GnomAD3 genomes AF: 0.0108 AC: 1642 AN: 152040 Hom.: 12 Cov.: 32

Gnomad AFR AF: 0.00353

Gnomad AMI AF: 0.0165

Gnomad AMR AF: 0.00459

Gnomad ASJ AF: 0.0291

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.0107

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0171

Gnomad OTH AF: 0.0115

GnomAD3 exomes AF: 0.0102 AC: 2552 AN: 251398 Hom.: 26 AF XY: 0.0102 AC XY: 1388 AN XY: 135890

Gnomad AFR exome AF: 0.00215

Gnomad AMR exome AF: 0.00399

Gnomad ASJ exome AF: 0.0288

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00105

Gnomad FIN exome AF: 0.0100

Gnomad NFE exome AF: 0.0156

Gnomad OTH exome AF: 0.00994

GnomAD4 exome AF: 0.0143 AC: 20871 AN: 1461878 Hom.: 178 Cov.: 33 AF XY: 0.0140 AC XY: 10155 AN XY: 727242

Gnomad4 AFR exome AF: 0.00221

Gnomad4 AMR exome AF: 0.00443

Gnomad4 ASJ exome AF: 0.0300

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00126

Gnomad4 FIN exome AF: 0.0118

Gnomad4 NFE exome AF: 0.0165

Gnomad4 OTH exome AF: 0.0127

GnomAD4 genome AF: 0.0108 AC: 1641 AN: 152158 Hom.: 12 Cov.: 32 AF XY: 0.00983 AC XY: 731 AN XY: 74396

Gnomad4 AFR AF: 0.00352

Gnomad4 AMR AF: 0.00458

Gnomad4 ASJ AF: 0.0291

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00186

Gnomad4 FIN AF: 0.0107

Gnomad4 NFE AF: 0.0171

Gnomad4 OTH AF: 0.0114

Alfa AF: 0.0152 Hom.: 22

Bravo AF: 0.0103

TwinsUK AF: 0.0132 AC: 49

ALSPAC AF: 0.0138 AC: 53

ESP6500AA AF: 0.00363 AC: 16

ESP6500EA AF: 0.0197 AC: 169

ExAC AF: 0.00975 AC: 1184

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.0158

EpiControl AF: 0.0146

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0048	T;.
Eigen	Benign	-0.046
Eigen_PC	Benign	-0.18
FATHMM_MKL	Benign	0.46	N
LIST_S2	Benign	0.57	T;T
MetaRNN	Benign	0.0044	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.3	M;M
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.98	N;N
REVEL	Benign	0.036
Sift	Uncertain	0.021	D;D
Sift4G	Benign	0.79	T;T
Polyphen		0.98	D;P
Vest4		0.32
MPC		0.23
ClinPred		0.012	T
GERP RS		2.9
Varity_R		0.083
gMVP		0.10

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: rs141499084; hg19: chr2-65299330; COSMIC: COSV99037226; COSMIC: COSV99037226;