22-50548455-C-A

Variant names:

• chr22-50548455-C-A
• NM_138433.5:c.2212C>A

Variant summary

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

The NM_138433.5(KLHDC7B):​c.2212C>A​(p.Gln738Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q738P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KLHDC7B NM_138433.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.576
• Publications: 0 publications found

Genes affected

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

KLHDC7B-DT (HGNC:53791): (KLHDC7B divergent transcript)

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 (MetaRNN=0.048483312).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_138433.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KLHDC7B	NM_138433.5	MANE Select	c.2212C>A	p.Gln738Lys	missense	Exon 1 of 1	NP_612442.3	A0A3B3ISF6
	KLHDC7B-DT	NR_199716.1		n.52+441G>T		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KLHDC7B	ENST00000648057.3	MANE Select	c.2212C>A	p.Gln738Lys	missense	Exon 1 of 1	ENSP00000497256.1	A0A3B3ISF6
	KLHDC7B-DT	ENST00000796178.1		n.99+441G>T		intron	N/A
	KLHDC7B-DT	ENST00000796179.1		n.30+369G>T		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1427596 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 706652

African (AFR) AF: 0.00 AC: 0 AN: 33134

American (AMR) AF: 0.00 AC: 0 AN: 38830

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25446

East Asian (EAS) AF: 0.00 AC: 0 AN: 38500

South Asian (SAS) AF: 0.00 AC: 0 AN: 81996

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49578

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5728

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1095314

Other (OTH) AF: 0.00 AC: 0 AN: 59070

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	0.13
DANN	Benign	0.55
DEOGEN2	Benign	0.0012	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.066	N
LIST_S2	Benign	0.34	T
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.048	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.34	N
PhyloP100		-0.58
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.48	N
REVEL	Benign	0.032
Sift	Benign	1.0	T
Sift4G	Benign	0.84	T
Polyphen		0.017	B
Vest4		0.042
MutPred		0.37		Gain of solvent accessibility (P = 4e-04)
MVP		0.57
ClinPred		0.025	T
GERP RS		-3.2
PromoterAI		-0.0014	Neutral
Varity_R		0.056
gMVP		0.15
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

hg19: chr22-50986884;