2-169735901-C-T

Position:

• chr2-169735901-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_144711.6(KLHL23):​c.887C>T​(p.Thr296Ile) 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 1,461,826 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: KLHL23 NM_144711.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.29

Genes affected

KLHL23 (HGNC:27506): (kelch like family member 23)

PHOSPHO2-KLHL23 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.35439098).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KLHL23	NM_144711.6	c.887C>T	p.Thr296Ile	missense_variant	2/4	ENST00000392647.7	NP_653312.2
PHOSPHO2-KLHL23	NR_144936.2	n.359-5484C>T		intron_variant, non_coding_transcript_variant
PHOSPHO2-KLHL23	NM_001199290.3	c.887C>T	p.Thr296Ile	missense_variant	4/6		NP_001186219.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KLHL23	ENST00000392647.7	c.887C>T	p.Thr296Ile	missense_variant	2/4	1	NM_144711.6	ENSP00000376419	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461826 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727204

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

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

Jan 05, 2022

The c.887C>T (p.T296I) alteration is located in exon 2 (coding exon 1) of the KLHL23 gene. This alteration results from a C to T substitution at nucleotide position 887, causing the threonine (T) at amino acid position 296 to be replaced by an isoleucine (I). 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	Uncertain	0.41
BayesDel_addAF	Benign	-0.018	T
BayesDel_noAF	Benign	-0.26
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.63	D;D;.
Eigen	Uncertain	0.20
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.82	.;T;T
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.35	T;T;T
MetaSVM	Uncertain	0.014	D
MutationAssessor	Uncertain	2.4	M;M;.
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-3.5	D;D;D
REVEL	Uncertain	0.34
Sift	Benign	0.037	D;D;D
Sift4G	Benign	0.17	T;T;T
Polyphen		0.0030	B;B;.
Vest4		0.23
MutPred		0.46		Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);.;
MVP		0.91
MPC		0.11
ClinPred		0.93	D
GERP RS		4.8
Varity_R		0.33
gMVP		0.49

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: chr2-170592411;