ENST00000526761.5:n.*320+6982T>C

Variant names:

• chr11-77522966-A-G
• rs2105803
• ENST00000526761.5:n.*320+6982T>C

Variant summary

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

The ENST00000526761.5(CLNS1A):​n.*320+6982T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.254 in 152,116 control chromosomes in the GnomAD database, including 5,455 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 0.25 (5455 hom., cov: 33)
• Consequence: CLNS1A ENST00000526761.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.231
• Publications: 3 publications found

Genes affected

CLNS1A (HGNC:2080): (chloride nucleotide-sensitive channel 1A) This gene encodes a protein that functions in multiple regulatory pathways. The encoded protein complexes with numerous cytosolic proteins and performs diverse functions including regulation of small nuclear ribonucleoprotein biosynthesis, platelet activation and cytoskeletal organization. The protein is also found associated with the plasma membrane where it functions as a chloride current regulator. Pseudogenes of this gene are found on chromosomes 1, 4 and 6. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2015]

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]

PAK1 Gene-Disease associations (from GenCC):

• intellectual developmental disorder with macrocephaly, seizures, and speech delay

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.469 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAK1	XM_024448560.2	c.-377+6982T>C		intron_variant	Intron 1 of 16		XP_024304328.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLNS1A	ENST00000526761.5	n.*320+6982T>C		intron_variant	Intron 5 of 5	3		ENSP00000475218.1

Frequencies

GnomAD3 genomes AF: 0.254 AC: 38646 AN: 151996 Hom.: 5442 Cov.: 33

Gnomad AFR AF: 0.236

Gnomad AMI AF: 0.469

Gnomad AMR AF: 0.413

Gnomad ASJ AF: 0.278

Gnomad EAS AF: 0.318

Gnomad SAS AF: 0.485

Gnomad FIN AF: 0.201

Gnomad MID AF: 0.377

Gnomad NFE AF: 0.212

Gnomad OTH AF: 0.246

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.254 AC: 38704 AN: 152116 Hom.: 5455 Cov.: 33 AF XY: 0.262 AC XY: 19489 AN XY: 74360

African (AFR) AF: 0.236 AC: 9801 AN: 41478

American (AMR) AF: 0.414 AC: 6318 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.278 AC: 962 AN: 3466

East Asian (EAS) AF: 0.319 AC: 1648 AN: 5166

South Asian (SAS) AF: 0.485 AC: 2342 AN: 4830

European-Finnish (FIN) AF: 0.201 AC: 2127 AN: 10580

Middle Eastern (MID) AF: 0.384 AC: 113 AN: 294

European-Non Finnish (NFE) AF: 0.212 AC: 14442 AN: 68006

Other (OTH) AF: 0.248 AC: 524 AN: 2112

Alfa AF: 0.253 Hom.: 898

Bravo AF: 0.264

Asia WGS AF: 0.423 AC: 1471 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	4.5
DANN	Benign	0.52
PhyloP100		0.23

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2105803; hg19: chr11-77234011;