2-169735063-A-G

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_144711.6(KLHL23):​c.49A>G​(p.Thr17Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000754 in 1,591,244 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. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000069 (0 hom.)
• Consequence: KLHL23 NM_144711.6 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0480

Genes affected

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

PHOSPHO2-KLHL23 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05048752).
• BP6: Variant 2-169735063-A-G is Benign according to our data. Variant chr2-169735063-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 2327849.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KLHL23	NM_144711.6	c.49A>G	p.Thr17Ala	missense_variant	Exon 2 of 4	ENST00000392647.7	NP_653312.2
PHOSPHO2-KLHL23	NM_001199290.3	c.49A>G	p.Thr17Ala	missense_variant	Exon 4 of 6		NP_001186219.1
PHOSPHO2-KLHL23	NR_144936.2	n.359-6322A>G		intron_variant	Intron 3 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KLHL23	ENST00000392647.7	c.49A>G	p.Thr17Ala	missense_variant	Exon 2 of 4	1	NM_144711.6	ENSP00000376419.2
KLHL23	ENST00000272797.8	c.49A>G	p.Thr17Ala	missense_variant	Exon 4 of 6	2		ENSP00000272797.4
KLHL23	ENST00000602521.1	c.-266-6322A>G		intron_variant	Intron 1 of 2	3		ENSP00000475081.1
KLHL23	ENST00000498202.6	c.-266-6322A>G		intron_variant	Intron 4 of 5	3		ENSP00000474581.1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152246 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000130 AC: 3 AN: 230542 AF XY: 0.0000241

Gnomad AFR exome AF: 0.0000628

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000926

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000695 AC: 10 AN: 1438998 Hom.: 0 Cov.: 30 AF XY: 0.00000560 AC XY: 4 AN XY: 714782

African (AFR) AF: 0.0000311 AC: 1 AN: 32150

American (AMR) AF: 0.0000263 AC: 1 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: 0.0000247 AC: 2 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: 0.00000543 AC: 6 AN: 1105128

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

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152246 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74382

African (AFR) AF: 0.0000241 AC: 1 AN: 41468

American (AMR) AF: 0.00 AC: 0 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68046

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.0000848 Hom.: 0

Bravo AF: 0.0000302

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Nov 18, 2022

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.055
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	1.7
DANN	Benign	0.32
DEOGEN2	Benign	0.015	T;T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.042	N
LIST_S2	Benign	0.42	.;T
M_CAP	Benign	0.0086	T
MetaRNN	Benign	0.050	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.47	N;N
PhyloP100		0.048
PrimateAI	Benign	0.24	T
PROVEAN	Benign	0.34	N;N
REVEL	Benign	0.11
Sift	Benign	0.92	T;T
Sift4G	Benign	0.21	T;T
Polyphen		0.0	B;B
Vest4		0.068
MutPred		0.31		Gain of catalytic residue at T17 (P = 0.0318);Gain of catalytic residue at T17 (P = 0.0318);
MVP		0.45
MPC		0.098
ClinPred		0.036	T
GERP RS		-11
PromoterAI		0.0011	Neutral
Varity_R		0.040
gMVP		0.19
Mutation Taster		=92/8	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Other links and lift over

dbSNP: rs1046372781; hg19: chr2-170591573;