1-960709-G-C

Variant names:

• chr1-960709-G-C
• NM_198317.3:c.16G>C

Variant summary

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

The NM_198317.3(KLHL17):​c.16G>C​(p.Glu6Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000083 in 1,204,118 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 8.3e-7 (0 hom.)
• Consequence: KLHL17 NM_198317.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.294

Genes affected

KLHL17 (HGNC:24023): (kelch like family member 17) The protein encoded by this gene is expressed in neurons of most regions of the brain. It contains an N-terminal BTB domain, which mediates dimerization of the protein, and a C-terminal Kelch domain, which mediates binding to F-actin. This protein may play a key role in the regulation of actin-based neuronal function. [provided by RefSeq, Aug 2010]

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=0.15260544).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KLHL17	NM_198317.3	c.16G>C	p.Glu6Gln	missense_variant	Exon 1 of 12	ENST00000338591.8	NP_938073.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KLHL17	ENST00000338591.8	c.16G>C	p.Glu6Gln	missense_variant	Exon 1 of 12	1	NM_198317.3	ENSP00000343930.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 8.30e-7 AC: 1 AN: 1204118 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 591666

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000212

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 05, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.16G>C (p.E6Q) alteration is located in exon 1 (coding exon 1) of the KLHL17 gene. This alteration results from a G to C substitution at nucleotide position 16, causing the glutamic acid (E) at amino acid position 6 to be replaced by a glutamine (Q). 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	0.13
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.024	T
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.48
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.58	T
M_CAP	Pathogenic	0.64	D
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N
PrimateAI	Pathogenic	0.93	D
PROVEAN	Benign	0.020	N
REVEL	Benign	0.078
Sift	Benign	0.068	T
Sift4G	Benign	0.25	T
Polyphen		0.48	P
Vest4		0.24
MutPred		0.22		Gain of MoRF binding (P = 0.0267);
MVP		0.66
ClinPred		0.10	T
GERP RS		1.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.11
gMVP		0.34

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-896089;