rs2069442

Variant names:

• chr7-151058118-G-C
• rs2069442
• ENST00000483786.5:c.-64+837G>C

Variant summary

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

The ENST00000483786.5(SLC4A2):​c.-64+837G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.292 in 555,224 control chromosomes in the GnomAD database, including 24,798 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 0.32 (8183 hom., cov: 34)
  • Exomes 𝑓: 0.28 (16615 hom.)
• Consequence: SLC4A2 ENST00000483786.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.353
• Publications: 19 publications found

Genes affected

SLC4A2 (HGNC:11028): (solute carrier family 4 member 2) This gene encodes a member of the anion exchanger family of membrane transport proteins. The encoded protein regulates intracellular pH, biliary bicarbonate secretion, and chloride uptake. Reduced expression of this gene may be associated with primary biliary cirrhosis (PBC) in human patients, while differential expression of this gene may be associated with malignant hepatocellular carcinoma, colon and gastric cancers. [provided by RefSeq, Nov 2016]

CDK5 (HGNC:1774): (cyclin dependent kinase 5) This gene encodes a proline-directed serine/threonine kinase that is a member of the cyclin-dependent kinase family of proteins. Unlike other members of the family, the protein encoded by this gene does not directly control cell cycle regulation. Instead the protein, which is predominantly expressed at high levels in mammalian postmitotic central nervous system neurons, functions in diverse processes such as synaptic plasticity and neuronal migration through phosphorylation of proteins required for cytoskeletal organization, endocytosis and exocytosis, and apoptosis. In humans, an allelic variant of the gene that results in undetectable levels of the protein has been associated with lethal autosomal recessive lissencephaly-7. Alternative splicing results in multiple transcript variants. [provided by RefSeq, May 2015]

CDK5 Gene-Disease associations (from GenCC):

• lissencephaly 7 with cerebellar hypoplasia

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), PanelApp Australia

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.57).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.415 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDK5	NM_004935.4	c.-270C>G		upstream_gene_variant		ENST00000485972.6	NP_004926.1
SLC4A2	NM_001199692.3	c.-1134G>C		upstream_gene_variant			NP_001186621.1
CDK5	NM_001164410.3	c.-270C>G		upstream_gene_variant			NP_001157882.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDK5	ENST00000485972.6	c.-270C>G		upstream_gene_variant		1	NM_004935.4	ENSP00000419782.1

Frequencies

GnomAD3 genomes AF: 0.320 AC: 48668 AN: 152120 Hom.: 8170 Cov.: 34

Gnomad AFR AF: 0.388

Gnomad AMI AF: 0.523

Gnomad AMR AF: 0.423

Gnomad ASJ AF: 0.314

Gnomad EAS AF: 0.313

Gnomad SAS AF: 0.252

Gnomad FIN AF: 0.294

Gnomad MID AF: 0.296

Gnomad NFE AF: 0.263

Gnomad OTH AF: 0.310

GnomAD4 exome AF: 0.281 AC: 113309 AN: 402988 Hom.: 16615 Cov.: 0 AF XY: 0.280 AC XY: 59143 AN XY: 211594

African (AFR) AF: 0.393 AC: 4036 AN: 10260

American (AMR) AF: 0.508 AC: 6364 AN: 12516

Ashkenazi Jewish (ASJ) AF: 0.306 AC: 3839 AN: 12564

East Asian (EAS) AF: 0.306 AC: 8271 AN: 27008

South Asian (SAS) AF: 0.260 AC: 9950 AN: 38332

European-Finnish (FIN) AF: 0.296 AC: 8411 AN: 28408

Middle Eastern (MID) AF: 0.303 AC: 547 AN: 1806

European-Non Finnish (NFE) AF: 0.262 AC: 65080 AN: 248460

Other (OTH) AF: 0.288 AC: 6811 AN: 23634

GnomAD4 genome AF: 0.320 AC: 48708 AN: 152236 Hom.: 8183 Cov.: 34 AF XY: 0.323 AC XY: 24045 AN XY: 74432

African (AFR) AF: 0.388 AC: 16113 AN: 41528

American (AMR) AF: 0.424 AC: 6483 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.314 AC: 1089 AN: 3472

East Asian (EAS) AF: 0.313 AC: 1621 AN: 5182

South Asian (SAS) AF: 0.250 AC: 1205 AN: 4822

European-Finnish (FIN) AF: 0.294 AC: 3118 AN: 10594

Middle Eastern (MID) AF: 0.295 AC: 86 AN: 292

European-Non Finnish (NFE) AF: 0.263 AC: 17863 AN: 68016

Other (OTH) AF: 0.309 AC: 653 AN: 2116

Alfa AF: 0.308 Hom.: 935

Bravo AF: 0.341

Asia WGS AF: 0.314 AC: 1091 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
CADD	Benign	12
DANN	Benign	0.85
PhyloP100		-0.35
PromoterAI		0.020	Neutral
Mutation Taster		=300/0	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: rs2069442; hg19: chr7-150755205; COSMIC: COSV52531161; COSMIC: COSV52531161;