chr1-161098767-C-A

Variant names:

• chr1-161098767-C-A
• rs1222275508
• NM_152366.5:c.232C>A

Variant summary

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

The NM_152366.5(KLHDC9):​c.232C>A​(p.Pro78Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000622 in 1,447,954 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 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. P78L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: KLHDC9 NM_152366.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.475
• 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: 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=0.061489582).

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.232C>A	p.Pro78Thr	missense	Exon 1 of 4	NP_689579.3
	KLHDC9	NM_001007255.3		c.232C>A	p.Pro78Thr	missense	Exon 1 of 4	NP_001007256.1	Q8NEP7-2
	KLHDC9	NR_033385.2		n.146C>A		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.232C>A	p.Pro78Thr	missense	Exon 1 of 4	ENSP00000356990.4	Q8NEP7-1
	KLHDC9	ENST00000392192.6	TSL:1	c.232C>A	p.Pro78Thr	missense	Exon 1 of 4	ENSP00000376030.2	Q8NEP7-2
	KLHDC9	ENST00000917942.1		c.232C>A	p.Pro78Thr	missense	Exon 1 of 4	ENSP00000588001.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00 AC: 0 AN: 220646 AF XY: 0.00

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000622 AC: 9 AN: 1447954 Hom.: 0 Cov.: 31 AF XY: 0.00000695 AC XY: 5 AN XY: 719246

African (AFR) AF: 0.00 AC: 0 AN: 33080

American (AMR) AF: 0.00 AC: 0 AN: 42814

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25810

East Asian (EAS) AF: 0.00 AC: 0 AN: 38758

South Asian (SAS) AF: 0.00 AC: 0 AN: 84632

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52222

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5742

European-Non Finnish (NFE) AF: 0.00000814 AC: 9 AN: 1105218

Other (OTH) AF: 0.00 AC: 0 AN: 59678

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	0.68
DANN	Benign	0.87
DEOGEN2	Benign	0.0075	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.012	N
LIST_S2	Benign	0.54	T
M_CAP	Benign	0.044	D
MetaRNN	Benign	0.061	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.90	L
PhyloP100		-0.47
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.14
Sift	Benign	0.52	T
Sift4G	Benign	0.48	T
Polyphen		0.0050	B
Vest4		0.11
MutPred		0.27		Loss of catalytic residue at P77 (P = 0.0144)
MVP		0.030
MPC		0.37
ClinPred		0.057	T
GERP RS		-2.8
PromoterAI		0.021	Neutral
Varity_R		0.078
gMVP		0.69
Mutation Taster		=95/5	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

dbSNP: rs1222275508; hg19: chr1-161068557;