1-161098770-C-G

Variant names:

• chr1-161098770-C-G
• rs745709628
• NM_152366.5:c.235C>G

Variant summary

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

The NM_152366.5(KLHDC9):​c.235C>G​(p.Arg79Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000691 in 1,447,292 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. R79C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: KLHDC9 NM_152366.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.92
• Publications: 0 publications found

Genes affected

KLHDC9 (HGNC:28489): (kelch domain containing 9) Enables cyclin binding activity. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

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_152366.5. 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
	KLHDC9	NM_152366.5	MANE Select	c.235C>G	p.Arg79Gly	missense	Exon 1 of 4	NP_689579.3
	KLHDC9	NM_001007255.3		c.235C>G	p.Arg79Gly	missense	Exon 1 of 4	NP_001007256.1	Q8NEP7-2
	KLHDC9	NR_033385.2		n.149C>G		non_coding_transcript_exon	Exon 2 of 5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KLHDC9	ENST00000368011.9	TSL:1 MANE Select	c.235C>G	p.Arg79Gly	missense	Exon 1 of 4	ENSP00000356990.4	Q8NEP7-1
	KLHDC9	ENST00000392192.6	TSL:1	c.235C>G	p.Arg79Gly	missense	Exon 1 of 4	ENSP00000376030.2	Q8NEP7-2
	KLHDC9	ENST00000917942.1		c.235C>G	p.Arg79Gly	missense	Exon 1 of 4	ENSP00000588001.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.91e-7 AC: 1 AN: 1447292 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 718904

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33060

American (AMR) AF: 0.00 AC: 0 AN: 42682

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25792

East Asian (EAS) AF: 0.00 AC: 0 AN: 38734

South Asian (SAS) AF: 0.00 AC: 0 AN: 84530

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52150

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5740

European-Non Finnish (NFE) AF: 9.05e-7 AC: 1 AN: 1104944

Other (OTH) AF: 0.00 AC: 0 AN: 59660

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.090	T
Eigen	Uncertain	0.23
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.74	T
M_CAP	Uncertain	0.19	D
MetaRNN	Uncertain	0.73	D
MetaSVM	Uncertain	-0.14	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		1.9
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-3.1	D
REVEL	Uncertain	0.58
Sift	Uncertain	0.025	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.97	D
Vest4		0.58
MutPred		0.37		Loss of methylation at R79 (P = 0.0306)
MVP		0.80
MPC		1.2
ClinPred		0.96	D
GERP RS		4.0
PromoterAI		0.012	Neutral
Varity_R		0.61
gMVP		0.93
Mutation Taster		=50/50

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

dbSNP: rs745709628; hg19: chr1-161068560;