chr7-151056377-A-G

Variant names:

• chr7-151056377-A-G
• rs1549759
• NM_004935.4:c.312+203T>C

Variant summary

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

The NM_004935.4(CDK5):​c.312+203T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.865 in 603,802 control chromosomes in the GnomAD database, including 226,290 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 0.88 (58761 hom., cov: 32)
  • Exomes 𝑓: 0.86 (167529 hom.)
• Consequence: CDK5 NM_004935.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.199
• Publications: 8 publications found

Genes affected

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=-0.84).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.935 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDK5	NM_004935.4	c.312+203T>C		intron_variant	Intron 5 of 11	ENST00000485972.6	NP_004926.1
CDK5	NM_001164410.3	c.312+203T>C		intron_variant	Intron 5 of 10		NP_001157882.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDK5	ENST00000485972.6	c.312+203T>C		intron_variant	Intron 5 of 11	1	NM_004935.4	ENSP00000419782.1

Frequencies

GnomAD3 genomes AF: 0.878 AC: 133531 AN: 152110 Hom.: 58706 Cov.: 32

Gnomad AFR AF: 0.929

Gnomad AMI AF: 0.845

Gnomad AMR AF: 0.897

Gnomad ASJ AF: 0.908

Gnomad EAS AF: 0.957

Gnomad SAS AF: 0.843

Gnomad FIN AF: 0.864

Gnomad MID AF: 0.911

Gnomad NFE AF: 0.840

Gnomad OTH AF: 0.875

GnomAD4 exome AF: 0.860 AC: 388364 AN: 451574 Hom.: 167529 Cov.: 4 AF XY: 0.859 AC XY: 204465 AN XY: 238110

African (AFR) AF: 0.932 AC: 11654 AN: 12508

American (AMR) AF: 0.912 AC: 17418 AN: 19104

Ashkenazi Jewish (ASJ) AF: 0.902 AC: 12494 AN: 13856

East Asian (EAS) AF: 0.977 AC: 30558 AN: 31264

South Asian (SAS) AF: 0.849 AC: 38623 AN: 45470

European-Finnish (FIN) AF: 0.863 AC: 25962 AN: 30074

Middle Eastern (MID) AF: 0.865 AC: 1713 AN: 1980

European-Non Finnish (NFE) AF: 0.838 AC: 227303 AN: 271160

Other (OTH) AF: 0.865 AC: 22639 AN: 26158

GnomAD4 genome AF: 0.878 AC: 133643 AN: 152228 Hom.: 58761 Cov.: 32 AF XY: 0.878 AC XY: 65347 AN XY: 74428

African (AFR) AF: 0.929 AC: 38590 AN: 41530

American (AMR) AF: 0.898 AC: 13718 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.908 AC: 3151 AN: 3470

East Asian (EAS) AF: 0.957 AC: 4956 AN: 5180

South Asian (SAS) AF: 0.843 AC: 4070 AN: 4830

European-Finnish (FIN) AF: 0.864 AC: 9169 AN: 10610

Middle Eastern (MID) AF: 0.918 AC: 270 AN: 294

European-Non Finnish (NFE) AF: 0.840 AC: 57092 AN: 68002

Other (OTH) AF: 0.877 AC: 1856 AN: 2116

Alfa AF: 0.861 Hom.: 92748

Bravo AF: 0.884

Asia WGS AF: 0.913 AC: 3173 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	1.9
DANN	Benign	0.55
PhyloP100		-0.20
Mutation Taster		=100/0	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: rs1549759; hg19: chr7-150753464;