Genetic Variant NM_014780.5:c.2416G>C (chr6-43046583-C-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_014780.5(CUL7):c.2416G>C(p.Glu806Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,461,856 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E806K) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

CUL7
NM_014780.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.66

Publications

0 publications found

Variant links:

Genes affected

CUL7 (HGNC:21024): (cullin 7) The protein encoded by this gene is a component of an E3 ubiquitin-protein ligase complex. The encoded protein interacts with TP53, CUL9, and FBXW8 proteins. Defects in this gene are a cause of 3M syndrome type 1 (3M1). Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2009]

CUL7 links:

KLC4 (HGNC:21624): (kinesin light chain 4) Predicted to be located in cytoplasm and microtubule. Predicted to be part of kinesin complex. [provided by Alliance of Genome Resources, Apr 2022]

KLC4 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014780.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CUL7	NM_014780.5	MANE Select	c.2416G>C	p.Glu806Gln	missense	Exon 11 of 26	NP_055595.2
CUL7	NM_001168370.2		c.2512G>C	p.Glu838Gln	missense	Exon 11 of 26	NP_001161842.2	A0A669KBH4
CUL7	NM_001374872.1		c.2512G>C	p.Glu838Gln	missense	Exon 11 of 26	NP_001361801.1	A0A669KBH4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CUL7	ENST00000265348.9	TSL:1 MANE Select	c.2416G>C	p.Glu806Gln	missense	Exon 11 of 26	ENSP00000265348.4	Q14999-1
CUL7	ENST00000674100.1		c.2512G>C	p.Glu838Gln	missense	Exon 11 of 26	ENSP00000501292.1	A0A669KBH4
CUL7	ENST00000674134.1		c.2512G>C	p.Glu838Gln	missense	Exon 11 of 26	ENSP00000501068.1	A0A669KBH4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000616

AC:

AN:

1461856

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727228

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33476

American (AMR)

AF:

0.00

AC:

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000809

AC:

AN:

1111990

Other (OTH)

AF:

0.00

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.414

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.48

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Uncertain

-0.070

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.41

Eigen

Pathogenic

0.82

Eigen_PC

Pathogenic

0.81

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Pathogenic

0.98

M_CAP

Uncertain

0.094

MetaRNN

Uncertain

0.60

MetaSVM

Uncertain

-0.26

MutationAssessor

Benign

1.5

PhyloP100

7.7

PrimateAI

Uncertain

0.63

PROVEAN

Benign

-1.7

REVEL

Benign

0.22

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0050

Polyphen

1.0

Vest4

0.55

MutPred

0.19

Gain of helix (P = 0.062)

MVP

0.83

MPC

0.77

ClinPred

0.96

GERP RS

5.5

Varity_R

0.40

gMVP

0.52

Mutation Taster

=57/43

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.25

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.25

Position offset: 18

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over