rs2070127

Positions:

• chr2-224481929-T-A
• chr2-224481929-T-C
• chr2-224481929-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The ENST00000264414.9(CUL3):​c.1992A>T​(p.Gln664His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. Q664Q) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CUL3 ENST00000264414.9 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.82

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), CUL3. . Gene score misZ 4.7538 (greater than the threshold 3.09). Trascript score misZ 5.1469 (greater than threshold 3.09). GenCC has associacion of gene with complex neurodevelopmental disorder, neurodevelopmental disorder with or without autism or seizures, pseudohypoaldosteronism type 2E.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CUL3	NM_003590.5	c.1992A>T	p.Gln664His	missense_variant	14/16	ENST00000264414.9	NP_003581.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CUL3	ENST00000264414.9	c.1992A>T	p.Gln664His	missense_variant	14/16	1	NM_003590.5	ENSP00000264414	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1438826 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 714326

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Uncertain	0.013	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	16
DANN	Uncertain	0.98
DEOGEN2	Benign	0.38	T;.;.;T;.
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.38
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.96	D;D;.;D;D
M_CAP	Benign	0.021	T
MetaRNN	Uncertain	0.56	D;D;D;D;D
MetaSVM	Benign	-0.66	T
MutationAssessor	Benign	0.85	L;.;.;.;.
MutationTaster	Benign	0.000013	P;P;P;P
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-1.2	N;N;N;.;N
REVEL	Uncertain	0.31
Sift	Benign	0.040	D;T;D;.;D
Sift4G	Benign	0.095	T;T;T;T;T
Polyphen		0.0020	B;B;.;.;.
Vest4		0.49
MutPred		0.46		Loss of MoRF binding (P = 0.0866);.;.;.;.;
MVP		0.89
MPC		1.1
ClinPred		0.56	D
GERP RS		2.1
Varity_R		0.17
gMVP		0.45

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

LitVar

Other links and lift over

dbSNP: rs2070127; hg19: chr2-225346646;