2-169735063-A-T

Variant names:

• chr2-169735063-A-T
• rs1046372781
• NM_144711.6:c.49A>T

Variant summary

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

The NM_144711.6(KLHL23):​c.49A>T​(p.Thr17Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000695 in 1,438,998 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 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. T17A) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: KLHL23 NM_144711.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0480
• Publications: 0 publications found

Genes affected

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

PHOSPHO2-KLHL23 (HGNC:):

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=0.040079057).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KLHL23	NM_144711.6	c.49A>T	p.Thr17Ser	missense_variant	Exon 2 of 4	ENST00000392647.7	NP_653312.2
PHOSPHO2-KLHL23	NM_001199290.3	c.49A>T	p.Thr17Ser	missense_variant	Exon 4 of 6		NP_001186219.1
PHOSPHO2-KLHL23	NR_144936.2	n.359-6322A>T		intron_variant	Intron 3 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KLHL23	ENST00000392647.7	c.49A>T	p.Thr17Ser	missense_variant	Exon 2 of 4	1	NM_144711.6	ENSP00000376419.2
KLHL23	ENST00000272797.8	c.49A>T	p.Thr17Ser	missense_variant	Exon 4 of 6	2		ENSP00000272797.4
KLHL23	ENST00000602521.1	c.-266-6322A>T		intron_variant	Intron 1 of 2	3		ENSP00000475081.1
KLHL23	ENST00000498202.6	c.-266-6322A>T		intron_variant	Intron 4 of 5	3		ENSP00000474581.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.95e-7 AC: 1 AN: 1438998 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 714782

African (AFR) AF: 0.00 AC: 0 AN: 32150

American (AMR) AF: 0.00 AC: 0 AN: 38002

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25006

East Asian (EAS) AF: 0.00 AC: 0 AN: 39544

South Asian (SAS) AF: 0.00 AC: 0 AN: 81010

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53098

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5616

European-Non Finnish (NFE) AF: 9.05e-7 AC: 1 AN: 1105128

Other (OTH) AF: 0.00 AC: 0 AN: 59444

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	0.21
DANN	Benign	0.12
DEOGEN2	Benign	0.013	T;T
Eigen	Benign	-1.9
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.051	N
LIST_S2	Benign	0.42	.;T
M_CAP	Benign	0.0052	T
MetaRNN	Benign	0.040	T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-1.4	N;N
PhyloP100		0.048
PrimateAI	Benign	0.24	T
PROVEAN	Benign	1.5	N;N
REVEL	Benign	0.12
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0	B;B
Vest4		0.10
MutPred		0.30		Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);
MVP		0.40
MPC		0.089
ClinPred		0.059	T
GERP RS		-11
PromoterAI		0.0049	Neutral
Varity_R		0.045
gMVP		0.16
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1046372781; hg19: chr2-170591573;