22-50548510-C-T

Variant names:

• chr22-50548510-C-T
• rs747124532
• NM_138433.5:c.2267C>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_138433.5(KLHDC7B):​c.2267C>T​(p.Pro756Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000498 in 1,404,400 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. 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. P756H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000050 (0 hom.)
• Consequence: KLHDC7B NM_138433.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.32

Genes affected

KLHDC7B (HGNC:25145): (kelch domain containing 7B)

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08745435).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KLHDC7B	NM_138433.5	c.2267C>T	p.Pro756Leu	missense_variant	Exon 1 of 1	ENST00000648057.3	NP_612442.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KLHDC7B	ENST00000648057.3	c.2267C>T	p.Pro756Leu	missense_variant	Exon 1 of 1		NM_138433.5	ENSP00000497256.1
KLHDC7B	ENST00000395676.4	c.344C>T	p.Pro115Leu	missense_variant	Exon 1 of 1	6		ENSP00000379034.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.0000129 AC: 2 AN: 154720 Hom.: 0 AF XY: 0.0000119 AC XY: 1 AN XY: 83750

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000855

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000498 AC: 7 AN: 1404400 Hom.: 0 Cov.: 34 AF XY: 0.00000721 AC XY: 5 AN XY: 693052

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: 0.0000874

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000228 Hom.: 0

ExAC AF: 0.0000281 AC: 3

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0078	.;T
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.78
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.42	T;T
M_CAP	Uncertain	0.095	D
MetaRNN	Benign	0.087	T;T
MetaSVM	Benign	-0.59	T
MutationAssessor	Benign	1.8	.;L
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.4	.;N
REVEL	Benign	0.13
Sift	Uncertain	0.0020	.;D
Sift4G	Uncertain	0.010	.;D
Polyphen		0.028	.;B
Vest4		0.13
MutPred		0.32		.;Loss of relative solvent accessibility (P = 0.0071);
MVP		0.46
ClinPred		0.14	T
GERP RS		3.4
Varity_R		0.049
gMVP		0.16

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: rs747124532; hg19: chr22-50986939;