rs61748654

Variant names:

• chr6-43046560-TT-CC
• rs61748654
• NM_014780.5:c.2438_2439delAAinsGG

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6 BA1

The NM_014780.5(CUL7):​c.2438_2439delAAinsGG​(p.Gln813Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. The variant is present in control chromosomes in GnomAd MNV project. The variant allele was found at a frequency of 0.976 in 276,009 alleles, including 134,934 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Benign in ClinVar. Synonymous variant affecting the same amino acid position (i.e. Q813Q) has been classified as Benign.

• Frequency: GnomAD MNV: 𝑓 0.98 Genomes: not found (cov: 31)
• Consequence: CUL7 NM_014780.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 1.49
• Publications: 9 publications found

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]

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]

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP6: Variant 6-43046560-TT-CC is Benign according to our data. Variant chr6-43046560-TT-CC is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 260435.
• BA1: GnomAdMnv highest population allele frequency = 0.976 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CUL7	NM_014780.5	MANE Select	c.2438_2439delAAinsGG	p.Gln813Arg	missense	N/A	NP_055595.2
	CUL7	NM_001168370.2		c.2534_2535delAAinsGG	p.Gln845Arg	missense	N/A	NP_001161842.2
	CUL7	NM_001374872.1		c.2534_2535delAAinsGG	p.Gln845Arg	missense	N/A	NP_001361801.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CUL7	ENST00000265348.9	TSL:1 MANE Select	c.2438_2439delAAinsGG	p.Gln813Arg	missense	N/A	ENSP00000265348.4
	CUL7	ENST00000674100.1		c.2534_2535delAAinsGG	p.Gln845Arg	missense	N/A	ENSP00000501292.1
	CUL7	ENST00000674134.1		c.2534_2535delAAinsGG	p.Gln845Arg	missense	N/A	ENSP00000501068.1

Frequencies

GnomAD3 genomes Cov.: 31

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 31

GnomAD MNV AF: 0.976 AC: 276009 Hom.: 134934

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	3M syndrome 1 (1)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.5

Splicing

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

Other links and lift over

dbSNP: rs61748654; hg19: chr6-43014298; COSMIC: COSV108089654;