rs1223164602

Variant names:

• chr13-69707667-G-T
• rs1223164602
• NM_020866.3:c.2145C>A

Variant summary

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

The NM_020866.3(KLHL1):​c.2145C>A​(p.Asn715Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,612,436 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N715H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: KLHL1 NM_020866.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.48
• Publications: 0 publications found

Genes affected

KLHL1 (HGNC:6352): (kelch like family member 1) The KLHL1 protein belongs to a family of actin-organizing proteins related to Drosophila Kelch (Nemes et al., 2000 [PubMed 10888605]).[supplied by OMIM, Feb 2010]

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=0.2152071).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KLHL1	NM_020866.3	c.2145C>A	p.Asn715Lys	missense_variant	Exon 10 of 11	ENST00000377844.9	NP_065917.1
KLHL1	NM_001286725.2	c.1962C>A	p.Asn654Lys	missense_variant	Exon 9 of 10		NP_001273654.1
KLHL1	XM_017020678.3	c.1626C>A	p.Asn542Lys	missense_variant	Exon 10 of 11		XP_016876167.1
KLHL1	XM_017020679.2	c.1476C>A	p.Asn492Lys	missense_variant	Exon 10 of 11		XP_016876168.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KLHL1	ENST00000377844.9	c.2145C>A	p.Asn715Lys	missense_variant	Exon 10 of 11	1	NM_020866.3	ENSP00000367075.4
KLHL1	ENST00000545028.2	c.1962C>A	p.Asn654Lys	missense_variant	Exon 9 of 10	2		ENSP00000439602.2

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 151882 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.00000399 AC: 1 AN: 250834 AF XY: 0.00

Gnomad AFR exome AF: 0.00

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: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1460554 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726566

African (AFR) AF: 0.00 AC: 0 AN: 33410

American (AMR) AF: 0.00 AC: 0 AN: 44588

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26064

East Asian (EAS) AF: 0.00 AC: 0 AN: 39678

South Asian (SAS) AF: 0.00 AC: 0 AN: 86206

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53396

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111116

Other (OTH) AF: 0.00 AC: 0 AN: 60338

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 151882 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74174

African (AFR) AF: 0.00 AC: 0 AN: 41400

American (AMR) AF: 0.00 AC: 0 AN: 15174

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5162

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67930

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.0000330 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 18, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2145C>A (p.N715K) alteration is located in exon 10 (coding exon 10) of the KLHL1 gene. This alteration results from a C to A substitution at nucleotide position 2145, causing the asparagine (N) at amino acid position 715 to be replaced by a lysine (K). 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	0.42
BayesDel_addAF	Benign	-0.072	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	19
DANN	Benign	0.87
DEOGEN2	Benign	0.40	T;.
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.16
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.90	D;D
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.22	T;T
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	0.98	L;.
PhyloP100		1.5
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-1.1	N;.
REVEL	Benign	0.17
Sift	Benign	0.69	T;.
Sift4G	Benign	0.63	T;T
Polyphen		0.26	B;.
Vest4		0.31
MutPred		0.58		Gain of catalytic residue at Q711 (P = 0.0102);.;
MVP		0.80
MPC		0.094
ClinPred		0.28	T
GERP RS		2.5
Varity_R		0.097
gMVP		0.60
Mutation Taster		=57/43	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: rs1223164602; hg19: chr13-70281799;