7-99385766-A-C

Position:

chr7-99385766-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4BS1_Supporting

The NM_005720.4(ARPC1B):c.52A>C(p.Lys18Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000013 in 1,610,182 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

ARPC1B
NM_005720.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 4.64

Variant links:

Genes affected

ARPC1B (HGNC:704): (actin related protein 2/3 complex subunit 1B) This gene encodes one of seven subunits of the human Arp2/3 protein complex. This subunit is a member of the SOP2 family of proteins and is most similar to the protein encoded by gene ARPC1A. The similarity between these two proteins suggests that they both may function as p41 subunit of the human Arp2/3 complex that has been implicated in the control of actin polymerization in cells. It is possible that the p41 subunit is involved in assembling and maintaining the structure of the Arp2/3 complex. Multiple versions of the p41 subunit may adapt the functions of the complex to different cell types or developmental stages. This protein also has a role in centrosomal homeostasis by being an activator and substrate of the Aurora A kinase. [provided by RefSeq, Mar 2011]

ARPC1B links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.3742745).

BS1

Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.0000123 (18/1458032) while in subpopulation MID AF= 0.000521 (3/5760). AF 95% confidence interval is 0.000141. There are 0 homozygotes in gnomad4_exome. There are 8 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARPC1B	NM_005720.4 linkuse as main transcript	c.52A>C	p.Lys18Gln	missense_variant	2/10	ENST00000646101.2	NP_005711.1
ARPC1B	XM_024446628.2 linkuse as main transcript	c.52A>C	p.Lys18Gln	missense_variant	2/10		XP_024302396.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARPC1B	ENST00000646101.2 linkuse as main transcript	c.52A>C	p.Lys18Gln	missense_variant	2/10		NM_005720.4	ENSP00000496599	P1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152150

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000165

AC:

AN:

242056

Hom.:

AF XY:

0.0000229

AC XY:

AN XY:

131076

show subpopulations

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000363

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000123

AC:

AN:

1458032

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

724984

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000117

Gnomad4 OTH exome

AF:

0.0000332

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152150

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74314

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000966

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 15, 2021

The c.52A>C (p.K18Q) alteration is located in exon 2 (coding exon 1) of the ARPC1B gene. This alteration results from a A to C substitution at nucleotide position 52, causing the lysine (K) at amino acid position 18 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 04, 2022

This sequence change replaces lysine, which is basic and polar, with glutamine, which is neutral and polar, at codon 18 of the ARPC1B protein (p.Lys18Gln). This variant is present in population databases (rs755884757, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with ARPC1B-related conditions. ClinVar contains an entry for this variant (Variation ID: 1416166). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt ARPC1B protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Benign

-0.32

CADD

Uncertain

DANN

Uncertain

0.98

DEOGEN2

Benign

0.024

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

Eigen

Uncertain

0.27

Eigen_PC

Uncertain

0.31

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.84

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

M_CAP

Benign

0.054

MetaRNN

Benign

0.37

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

MetaSVM

Benign

-0.65

MutationAssessor

Benign

2.0

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

MutationTaster

Benign

1.0

N;D;D

PrimateAI

Uncertain

0.73

PROVEAN

Benign

-1.9

.;N;N;.;N;N;N;D;N;N;N;N;N;.

REVEL

Benign

0.12

Sift

Benign

0.44

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

Sift4G

Benign

0.43

.;T;T;.;T;T;T;D;T;T;T;T;T;.

Polyphen

0.21

.;.;.;B;B;B;.;.;.;B;B;B;B;B

Vest4

0.31

MutPred

0.48

.;Loss of ubiquitination at K18 (P = 0.0155);Loss of ubiquitination at K18 (P = 0.0155);Loss of ubiquitination at K18 (P = 0.0155);Loss of ubiquitination at K18 (P = 0.0155);Loss of ubiquitination at K18 (P = 0.0155);Loss of ubiquitination at K18 (P = 0.0155);Loss of ubiquitination at K18 (P = 0.0155);Loss of ubiquitination at K18 (P = 0.0155);Loss of ubiquitination at K18 (P = 0.0155);Loss of ubiquitination at K18 (P = 0.0155);Loss of ubiquitination at K18 (P = 0.0155);Loss of ubiquitination at K18 (P = 0.0155);Loss of ubiquitination at K18 (P = 0.0155);

MVP

0.68

MPC

0.45

ClinPred

0.38

GERP RS

4.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.39

gMVP

0.45

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

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