6-73224169-G-C

Position:

• chr6-73224169-G-C

Variant summary

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

The ENST00000370388.4(KHDC1L):​c.292C>G​(p.Arg98Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000256 in 1,406,480 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.000026 (0 hom.)
• Consequence: KHDC1L ENST00000370388.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.25

Genes affected

KHDC1L (HGNC:37274): (KH domain containing 1 like) Predicted to enable RNA binding activity and identical protein binding activity. Predicted to be involved in activation of cysteine-type endopeptidase activity involved in apoptotic process. Predicted to be active in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

LOC122539213 (HGNC:):

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=0.13451877).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KHDC1L	NM_001126063.3	c.292C>G	p.Arg98Gly	missense_variant	2/3	ENST00000370388.4	NP_001119535.1
LOC122539213	NR_173146.1	n.1264C>G		non_coding_transcript_exon_variant	6/7
LOC122539213	NR_173145.1	n.1471C>G		non_coding_transcript_exon_variant	7/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KHDC1L	ENST00000370388.4	c.292C>G	p.Arg98Gly	missense_variant	2/3	1	NM_001126063.3	ENSP00000359415	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.0000256 AC: 36 AN: 1406480 Hom.: 0 Cov.: 31 AF XY: 0.0000259 AC XY: 18 AN XY: 694534

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000787

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000554

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ExAC AF: 0.00000840 AC: 1

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 05, 2022

The c.292C>G (p.R98G) alteration is located in exon 2 (coding exon 2) of the KHDC1L gene. This alteration results from a C to G substitution at nucleotide position 292, causing the arginine (R) at amino acid position 98 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	15
DANN	Benign	0.94
DEOGEN2	Benign	0.095	T
Eigen	Benign	-0.73
Eigen_PC	Benign	-0.84
FATHMM_MKL	Benign	0.066	N
LIST_S2	Benign	0.54	T
M_CAP	Benign	0.0035	T
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.24	T
PROVEAN	Pathogenic	-5.6	D
REVEL	Benign	0.034
Sift	Benign	0.047	D
Sift4G	Uncertain	0.025	D
Polyphen		0.28	B
Vest4		0.27
MutPred		0.33		Loss of MoRF binding (P = 0.0064);
MVP		0.11
MPC		0.064
ClinPred		0.32	T
GERP RS		1.9
Varity_R		0.21
gMVP		0.079

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: rs765833855; hg19: chr6-73933892; COSMIC: COSV64893672; COSMIC: COSV64893672;