2-23562477-C-A

Variant names:

• chr2-23562477-C-A
• rs1667475692
• NM_052920.2:c.281C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_052920.2(KLHL29):​c.281C>A​(p.Thr94Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000000723 in 1,383,436 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: KLHL29 NM_052920.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.00
• Publications: 0 publications found

Genes affected

KLHL29 (HGNC:29404): (kelch like family member 29)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.23551893).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_052920.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KLHL29	NM_052920.2	MANE Select	c.281C>A	p.Thr94Asn	missense	Exon 3 of 14	NP_443152.1	Q96CT2-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KLHL29	ENST00000486442.6	TSL:5 MANE Select	c.281C>A	p.Thr94Asn	missense	Exon 3 of 14	ENSP00000420659.1	Q96CT2-1
	KLHL29	ENST00000489446.1	TSL:1	n.362C>A		non_coding_transcript_exon	Exon 2 of 4
	KLHL29	ENST00000869654.1		c.281C>A	p.Thr94Asn	missense	Exon 2 of 13	ENSP00000539713.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.23e-7 AC: 1 AN: 1383436 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 682722

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 31574

American (AMR) AF: 0.00 AC: 0 AN: 35688

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25160

East Asian (EAS) AF: 0.00 AC: 0 AN: 35722

South Asian (SAS) AF: 0.00 AC: 0 AN: 79186

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34060

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5484

European-Non Finnish (NFE) AF: 9.27e-7 AC: 1 AN: 1078704

Other (OTH) AF: 0.00 AC: 0 AN: 57858

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.020	T
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.70	T
M_CAP	Benign	0.081	D
MetaRNN	Benign	0.24	T
MetaSVM	Uncertain	-0.21	T
MutationAssessor	Benign	0.34	N
PhyloP100		4.0
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-0.87	N
REVEL	Benign	0.17
Sift	Uncertain	0.0040	D
Sift4G	Benign	0.18	T
Vest4		0.20
MutPred		0.22		Loss of glycosylation at T94 (P = 0.0019)
MVP		0.69
ClinPred		0.83	D
GERP RS		3.8
Varity_R		0.22
gMVP		0.20
Mutation Taster		=77/23	polymorphism

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

Other links and lift over

dbSNP: rs1667475692; hg19: chr2-23785347;