Genetic Variant CEP44:p.Arg82His (chr4-174303710-G-A) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_001040157.3(CEP44):c.245G>A(p.Arg82His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000753 in 1,521,514 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R82C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00072 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00076 ( 2 hom. )

Consequence

CEP44
NM_001040157.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.81

Variant links:

Genes affected

CEP44 (HGNC:29356): (centrosomal protein 44) Enables microtubule binding activity. Involved in centriole replication and centriole-centriole cohesion. Located in centriole; centrosome; and spindle pole. [provided by Alliance of Genome Resources, Apr 2022]

CEP44 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.018687427).

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CEP44	NM_001040157.3 link	c.245G>A	p.Arg82His	missense_variant	Exon 5 of 12	ENST00000503780.6	NP_001035247.1	Q9C0F1-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CEP44	ENST00000503780.6 link	c.245G>A	p.Arg82His	missense_variant	Exon 5 of 12	1	NM_001040157.3	ENSP00000423153.1		Q9C0F1-1

Frequencies

GnomAD3 genomes

AF:

0.000730

AC:

111

AN:

152110

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000217

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

Gnomad ASJ

AF:

0.00663

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.0000945

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00101

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000829

AC:

197

AN:

237718

Hom.:

AF XY:

0.000909

AC XY:

117

AN XY:

128698

show subpopulations

Gnomad AFR exome

AF:

0.0000653

Gnomad AMR exome

AF:

0.000452

Gnomad ASJ exome

AF:

0.00648

Gnomad EAS exome

AF:

0.0000570

Gnomad SAS exome

AF:

0.000144

Gnomad FIN exome

AF:

0.0000467

Gnomad NFE exome

AF:

0.000986

Gnomad OTH exome

AF:

0.00106

GnomAD4 exome

AF:

0.000756

AC:

1035

AN:

1369288

Hom.:

Cov.:

AF XY:

0.000757

AC XY:

511

AN XY:

675250

show subpopulations

Gnomad4 AFR exome

AF:

0.0000944

Gnomad4 AMR exome

AF:

0.000504

Gnomad4 ASJ exome

AF:

0.00629

Gnomad4 EAS exome

AF:

0.0000522

Gnomad4 SAS exome

AF:

0.000136

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000746

Gnomad4 OTH exome

AF:

0.000969

GnomAD4 genome

AF:

0.000723

AC:

110

AN:

152226

Hom.:

Cov.:

AF XY:

0.000699

AC XY:

AN XY:

74426

show subpopulations

Gnomad4 AFR

AF:

0.000217

Gnomad4 AMR

AF:

0.000327

Gnomad4 ASJ

AF:

0.00663

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.0000945

Gnomad4 NFE

AF:

0.00101

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.00126

Hom.:

Bravo

AF:

0.000688

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00163

AC:

ExAC

AF:

0.000873

AC:

106

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 16, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.245G>A (p.R82H) alteration is located in exon 5 (coding exon 3) of the CEP44 gene. This alteration results from a G to A substitution at nucleotide position 245, causing the arginine (R) at amino acid position 82 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.92

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Benign

-0.11

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.35

T;T;.;T;T;T;T;.

Eigen

Uncertain

0.49

Eigen_PC

Uncertain

0.52

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.96

.;.;.;D;D;D;D;D

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.019

T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.40

MutationAssessor

Pathogenic

3.1

M;.;M;.;.;.;M;M

PrimateAI

Uncertain

0.58

PROVEAN

Pathogenic

-4.6

D;D;D;D;D;D;D;D

REVEL

Uncertain

0.43

Sift

Uncertain

0.0020

D;D;D;D;D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D;D;D;D;D

Polyphen

0.76

P;.;P;.;.;.;P;P

Vest4

0.71

MVP

0.84

MPC

0.49

ClinPred

0.15

GERP RS

4.8

Varity_R

0.66

gMVP

0.80

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.15

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over