3-183518318-T-G

Variant names:

• chr3-183518318-T-G
• rs12496193
• NM_130446.4:c.459+9527A>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_130446.4(KLHL6):​c.459+9527A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.512 in 151,952 control chromosomes in the GnomAD database, including 20,537 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.51 (20537 hom., cov: 31)
• Consequence: KLHL6 NM_130446.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0800
• Publications: 8 publications found

Genes affected

KLHL6 (HGNC:18653): (kelch like family member 6) This gene encodes a member of the kelch-like (KLHL) family of proteins, which is involved in B-lymphocyte antigen receptor signaling and germinal-center B-cell maturation. The encoded protein contains an N-terminal broad-complex, tramtrack and bric a brac (BTB) domain that facilitates protein binding and dimerization, a BTB and C-terminal kelch (BACK) domain, and six C-terminal kelch repeat domains. Naturally occurring mutations in this gene are associated with chronic lymphocytic leukemia. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2017]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.578 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_130446.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KLHL6	NM_130446.4	MANE Select	c.459+9527A>C		intron	N/A	NP_569713.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KLHL6	ENST00000341319.8	TSL:1 MANE Select	c.459+9527A>C		intron	N/A	ENSP00000341342.3
	KLHL6	ENST00000468734.1	TSL:1	n.426+9527A>C		intron	N/A	ENSP00000433734.1
	KLHL6	ENST00000489245.5	TSL:1	n.471+9527A>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.511 AC: 77656 AN: 151834 Hom.: 20513 Cov.: 31

Gnomad AFR AF: 0.403

Gnomad AMI AF: 0.512

Gnomad AMR AF: 0.481

Gnomad ASJ AF: 0.513

Gnomad EAS AF: 0.353

Gnomad SAS AF: 0.442

Gnomad FIN AF: 0.636

Gnomad MID AF: 0.332

Gnomad NFE AF: 0.583

Gnomad OTH AF: 0.512

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.512 AC: 77726 AN: 151952 Hom.: 20537 Cov.: 31 AF XY: 0.509 AC XY: 37823 AN XY: 74242

African (AFR) AF: 0.403 AC: 16696 AN: 41434

American (AMR) AF: 0.481 AC: 7339 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.513 AC: 1778 AN: 3468

East Asian (EAS) AF: 0.353 AC: 1829 AN: 5176

South Asian (SAS) AF: 0.442 AC: 2121 AN: 4804

European-Finnish (FIN) AF: 0.636 AC: 6716 AN: 10558

Middle Eastern (MID) AF: 0.330 AC: 97 AN: 294

European-Non Finnish (NFE) AF: 0.583 AC: 39596 AN: 67932

Other (OTH) AF: 0.516 AC: 1090 AN: 2112

Alfa AF: 0.555 Hom.: 99696

Bravo AF: 0.496

Asia WGS AF: 0.422 AC: 1468 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	2.5
DANN	Benign	0.67
PhyloP100		0.080
Mutation Taster		=100/0	polymorphism (auto)

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: rs12496193; hg19: chr3-183236106;