chr1-205337482-C-G

Variant names:

• chr1-205337482-C-G
• rs577860092
• NM_018203.3:c.970G>C

Variant summary

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

The NM_018203.3(KLHDC8A):​c.970G>C​(p.Val324Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,796 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 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. V324I) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: KLHDC8A NM_018203.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.56
• Publications: 1 publications found

Genes affected

KLHDC8A (HGNC:25573): (kelch domain containing 8A) This gene encodes a kelch domain-containing protein which is upregulated in cancer. Upregulated expression of the encoded protein may provide an alternative pathway for tumors to maintain aggressiveness in the absence of epidermal growth factor receptor dependence. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2012]

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=0.023711264).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018203.3. 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
	KLHDC8A	NM_018203.3	MANE Select	c.970G>C	p.Val324Leu	missense	Exon 6 of 6	NP_060673.1	Q8IYD2
	KLHDC8A	NM_001271863.2		c.970G>C	p.Val324Leu	missense	Exon 9 of 9	NP_001258792.1	Q8IYD2
	KLHDC8A	NM_001271864.2		c.970G>C	p.Val324Leu	missense	Exon 7 of 7	NP_001258793.1	Q8IYD2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KLHDC8A	ENST00000367155.8	TSL:2 MANE Select	c.970G>C	p.Val324Leu	missense	Exon 6 of 6	ENSP00000356123.3	Q8IYD2
	KLHDC8A	ENST00000941910.1		c.994G>C	p.Val332Leu	missense	Exon 6 of 6	ENSP00000611969.1
	KLHDC8A	ENST00000367156.7	TSL:2	c.970G>C	p.Val324Leu	missense	Exon 9 of 9	ENSP00000356124.3	Q8IYD2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251340 AF XY: 0.00000736

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: 0.0000462

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461796 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727196

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5724

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111986

Other (OTH) AF: 0.00 AC: 0 AN: 60386

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	0.0010
DANN	Benign	0.64
DEOGEN2	Benign	0.033	T
Eigen	Benign	-2.0
Eigen_PC	Benign	-2.0
FATHMM_MKL	Benign	0.041	N
LIST_S2	Benign	0.65	T
M_CAP	Benign	0.0058	T
MetaRNN	Benign	0.024	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-0.69	N
PhyloP100		-3.6
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.10	N
REVEL	Benign	0.14
Sift	Benign	0.71	T
Sift4G	Benign	0.79	T
Polyphen		0.0	B
Vest4		0.044
MutPred		0.42		Loss of methylation at K325 (P = 0.0358)
MVP		0.48
MPC		0.42
ClinPred		0.034	T
GERP RS		-11
Varity_R		0.035
gMVP		0.22
Mutation Taster		=89/11	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: rs577860092; hg19: chr1-205306610;