11-77332855-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PM5 PP2 PP5

The NM_002576.5(PAK1):c.1426A>G(p.Ile476Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I476T) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 29)
• Consequence: PAK1 NM_002576.5 missense
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.64

Genes affected

PAK1 (HGNC:8590): (p21 (RAC1) activated kinase 1) This gene encodes a family member of serine/threonine p21-activating kinases, known as PAK proteins. These proteins are critical effectors that link RhoGTPases to cytoskeleton reorganization and nuclear signaling, and they serve as targets for the small GTP binding proteins Cdc42 and Rac. This specific family member regulates cell motility and morphology. Mutations in this gene have been associated with macrocephaly, seizures, and speech delay. Overexpression of this gene is also reported in many cancer types, and particularly in breast cancer. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2020]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a helix (size 10) in uniprot entity PAK1_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_002576.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-77332854-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 807646.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant where missense usually causes diseases, PAK1
• PP5: Variant 11-77332855-T-C is Pathogenic according to our data. Variant chr11-77332855-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2506574.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PAK1	NM_002576.5	c.1426A>G	p.Ile476Val	missense_variant	14/15	ENST00000356341.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PAK1	ENST00000356341.8	c.1426A>G	p.Ile476Val	missense_variant	14/15	1	NM_002576.5	P1

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 29

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Intellectual developmental disorder with macrocephaly, seizures, and speech delay Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Pediatric Neurology, Shengjing Hospital of China Medical University

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Uncertain	0.026	T
BayesDel_noAF	Benign	-0.20
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Benign	0.14	T;T;.;T
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D;D;D;D
M_CAP	Benign	0.017	T
MetaRNN	Uncertain	0.72	D;D;D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.83	L;.;L;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-0.92	N;N;N;N
REVEL	Uncertain	0.33
Sift	Uncertain	0.014	D;D;D;D
Sift4G	Uncertain	0.019	D;D;D;D
Polyphen		0.33	B;D;D;B
Vest4		0.77
MutPred		0.78		Gain of methylation at R471 (P = 0.2086);Gain of methylation at R471 (P = 0.2086);Gain of methylation at R471 (P = 0.2086);.;
MVP		0.62
MPC		1.8
ClinPred		0.78	D
GERP RS		5.9
Varity_R		0.47
gMVP		0.58

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-77043900;