rs10498163

Variant names:

• chr2-224569728-A-C
• rs10498163
• ENST00000409096.5:c.-46T>G

Your query was ambiguous. Multiple possible variants found:

• chr2-224569728-A-C
• chr2-224569728-A-G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The ENST00000409096.5(CUL3):​c.-46T>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000941 in 1,062,418 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 31)
  • Exomes 𝑓: 9.4e-7 (0 hom.)
• Consequence: CUL3 ENST00000409096.5 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.835
• Publications: 0 publications found

Genes affected

CUL3 (HGNC:2553): (cullin 3) This gene encodes a member of the cullin protein family. The encoded protein plays a critical role in the polyubiquitination and subsequent degradation of specific protein substrates as the core component and scaffold protein of an E3 ubiquitin ligase complex. Complexes including the encoded protein may also play a role in late endosome maturation. Mutations in this gene are a cause of type 2E pseudohypoaldosteronism. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Mar 2012]

CUL3 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• neurodevelopmental disorder with or without autism or seizures

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• pseudohypoaldosteronism type 2E

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CUL3	NM_003590.5	c.67-11872T>G		intron_variant	Intron 1 of 15	ENST00000264414.9	NP_003581.1
CUL3	NM_001257198.2	c.45T>G	p.His15Gln	missense_variant	Exon 1 of 16		NP_001244127.1
CUL3	NM_001257197.2	c.66+15216T>G		intron_variant	Intron 1 of 14		NP_001244126.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CUL3	ENST00000409096.5	c.-46T>G		5_prime_UTR_variant	Exon 1 of 16	1		ENSP00000387200.1
CUL3	ENST00000264414.9	c.67-11872T>G		intron_variant	Intron 1 of 15	1	NM_003590.5	ENSP00000264414.4
CUL3	ENST00000344951.8	c.66+15216T>G		intron_variant	Intron 1 of 14	2		ENSP00000343601.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 9.41e-7 AC: 1 AN: 1062418 Hom.: 0 Cov.: 20 AF XY: 0.00000192 AC XY: 1 AN XY: 520768

African (AFR) AF: 0.00 AC: 0 AN: 20600

American (AMR) AF: 0.00 AC: 0 AN: 17380

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13898

East Asian (EAS) AF: 0.00 AC: 0 AN: 8220

South Asian (SAS) AF: 0.00 AC: 0 AN: 66016

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 11464

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4114

European-Non Finnish (NFE) AF: 0.00000113 AC: 1 AN: 882702

Other (OTH) AF: 0.00 AC: 0 AN: 38024

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	9.0
DANN	Benign	0.66
PhyloP100		0.83
PromoterAI		0.0075	Neutral

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs10498163; hg19: chr2-225434445;