20-9566371-C-G

Variant names:

• chr20-9566371-C-G
• rs11700112
• NM_177990.4:c.1004G>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_177990.4(PAK5):​c.1004G>C​(p.Arg335Pro) variant causes a missense change. The variant allele was found at a frequency of 0.0995 in 1,612,162 control chromosomes in the GnomAD database, including 9,698 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.089 (750 hom., cov: 31)
  • Exomes 𝑓: 0.10 (8948 hom.)
• Consequence: PAK5 NM_177990.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.17
• Publications: 25 publications found

Genes affected

PAK5 (HGNC:15916): (p21 (RAC1) activated kinase 5) The protein encoded by this gene is a member of the PAK family of Ser/Thr protein kinases. PAK family members are known to be effectors of Rac/Cdc42 GTPases, which have been implicated in the regulation of cytoskeletal dynamics, proliferation, and cell survival signaling. This kinase contains a CDC42/Rac1 interactive binding (CRIB) motif, and has been shown to bind CDC42 in the presence of GTP. This kinase is predominantly expressed in brain. It is capable of promoting neurite outgrowth, and thus may play a role in neurite development. This kinase is associated with microtubule networks and induces microtubule stabilization. The subcellular localization of this kinase is tightly regulated during cell cycle progression. Alternatively spliced transcript variants encoding the same protein have been described. [provided by RefSeq, Jul 2008]

ENSG00000286740 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0025826693).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.226 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAK5	NM_177990.4	c.1004G>C	p.Arg335Pro	missense_variant	Exon 5 of 10	ENST00000353224.10	NP_817127.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAK5	ENST00000353224.10	c.1004G>C	p.Arg335Pro	missense_variant	Exon 5 of 10	1	NM_177990.4	ENSP00000322957.5
PAK5	ENST00000378423.5	c.1004G>C	p.Arg335Pro	missense_variant	Exon 6 of 11	1		ENSP00000367679.1
PAK5	ENST00000378429.3	c.1004G>C	p.Arg335Pro	missense_variant	Exon 6 of 11	1		ENSP00000367686.3
ENSG00000286740	ENST00000657954.2	n.161+3270C>G		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes AF: 0.0891 AC: 13531 AN: 151856 Hom.: 744 Cov.: 31

Gnomad AFR AF: 0.0460

Gnomad AMI AF: 0.0846

Gnomad AMR AF: 0.147

Gnomad ASJ AF: 0.105

Gnomad EAS AF: 0.237

Gnomad SAS AF: 0.0709

Gnomad FIN AF: 0.0948

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.0905

Gnomad OTH AF: 0.104

GnomAD2 exomes AF: 0.124 AC: 31022 AN: 250292 AF XY: 0.115

Gnomad AFR exome AF: 0.0475

Gnomad AMR exome AF: 0.274

Gnomad ASJ exome AF: 0.116

Gnomad EAS exome AF: 0.235

Gnomad FIN exome AF: 0.0944

Gnomad NFE exome AF: 0.0947

Gnomad OTH exome AF: 0.116

GnomAD4 exome AF: 0.101 AC: 146830 AN: 1460188 Hom.: 8948 Cov.: 33 AF XY: 0.0992 AC XY: 72022 AN XY: 726388

African (AFR) AF: 0.0471 AC: 1575 AN: 33468

American (AMR) AF: 0.259 AC: 11598 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.114 AC: 2965 AN: 26100

East Asian (EAS) AF: 0.253 AC: 10026 AN: 39682

South Asian (SAS) AF: 0.0633 AC: 5452 AN: 86192

European-Finnish (FIN) AF: 0.0967 AC: 5105 AN: 52766

Middle Eastern (MID) AF: 0.116 AC: 668 AN: 5766

European-Non Finnish (NFE) AF: 0.0930 AC: 103334 AN: 1111138

Other (OTH) AF: 0.101 AC: 6107 AN: 60358

GnomAD4 genome AF: 0.0891 AC: 13547 AN: 151974 Hom.: 750 Cov.: 31 AF XY: 0.0902 AC XY: 6699 AN XY: 74296

African (AFR) AF: 0.0460 AC: 1906 AN: 41438

American (AMR) AF: 0.148 AC: 2255 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.105 AC: 365 AN: 3468

East Asian (EAS) AF: 0.237 AC: 1216 AN: 5132

South Asian (SAS) AF: 0.0702 AC: 338 AN: 4818

European-Finnish (FIN) AF: 0.0948 AC: 1003 AN: 10576

Middle Eastern (MID) AF: 0.0646 AC: 19 AN: 294

European-Non Finnish (NFE) AF: 0.0905 AC: 6148 AN: 67956

Other (OTH) AF: 0.105 AC: 220 AN: 2102

Alfa AF: 0.0921 Hom.: 488

Bravo AF: 0.0997

TwinsUK AF: 0.0941 AC: 349

ALSPAC AF: 0.0957 AC: 369

ESP6500AA AF: 0.0533 AC: 235

ESP6500EA AF: 0.0947 AC: 814

ExAC AF: 0.116 AC: 14046

Asia WGS AF: 0.164 AC: 569 AN: 3478

EpiCase AF: 0.100

EpiControl AF: 0.0981

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.46
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.16	T;T;T
Eigen	Benign	0.12
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.82	.;.;T
MetaRNN	Benign	0.0026	T;T;T
MetaSVM	Benign	-1.2	T
PhyloP100		7.2
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-0.12	N;N;N
REVEL	Benign	0.13
Sift	Uncertain	0.0090	D;D;D
Sift4G	Benign	0.23	T;T;T
Polyphen		0.0	B;B;B
Vest4		0.30
MPC		0.51
ClinPred		0.035	T
GERP RS		5.0
Varity_R		0.33
gMVP		0.38
Mutation Taster		=99/1	polymorphism (auto)

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: rs11700112; hg19: chr20-9547018; COSMIC: COSV62021705;