13-52072067-T-C

Variant names:

• chr13-52072067-T-C
• rs149641412
• NM_001365552.1:c.1726A>G

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_001365552.1(NEK5):​c.1726A>G​(p.Met576Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0035 in 1,610,050 control chromosomes in the GnomAD database, including 12 homozygotes. 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 0.0025 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0036 (10 hom.)
• Consequence: NEK5 NM_001365552.1 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.41

Genes affected

NEK5 (HGNC:7748): (NIMA related kinase 5) Predicted to enable ATP binding activity; metal ion binding activity; and protein kinase activity. Predicted to be involved in protein phosphorylation. Predicted to act upstream of or within positive regulation of cysteine-type endopeptidase activity and positive regulation of striated muscle cell differentiation. [provided by Alliance of Genome Resources, Apr 2022]

ALG11 (HGNC:32456): (ALG11 alpha-1,2-mannosyltransferase) This gene encodes a GDP-Man:Man3GlcNAc2-PP-dolichol-alpha1,2-mannosyltransferase which is localized to the cytosolic side of the endoplasmic reticulum (ER) and catalyzes the transfer of the fourth and fifth mannose residue from GDP-mannose (GDP-Man) to Man3GlcNAc2-PP-dolichol and Man4GlcNAc2-PP-dolichol resulting in the production of Man5GlcNAc2-PP-dolichol. Mutations in this gene are associated with congenital disorder of glycosylation type Ip (CDGIP). This gene overlaps but is distinct from the UTP14, U3 small nucleolar ribonucleoprotein, homolog C (yeast) gene. A pseudogene of the GDP-Man:Man3GlcNAc2-PP-dolichol-alpha1,2-mannosyltransferase has been identified on chromosome 19. [provided by RefSeq, Aug 2010]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004542917).
• BP6: Variant 13-52072067-T-C is Benign according to our data. Variant chr13-52072067-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 2643825.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEK5	NM_001365552.1	c.1726A>G	p.Met576Val	missense_variant	Exon 20 of 24	ENST00000684899.1	NP_001352481.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NEK5	ENST00000684899.1	c.1726A>G	p.Met576Val	missense_variant	Exon 20 of 24		NM_001365552.1	ENSP00000509632.1

Frequencies

GnomAD3 genomes AF: 0.00251 AC: 382 AN: 152228 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000651

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00124

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00424

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00423

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.00259 AC: 645 AN: 248956 Hom.: 1 AF XY: 0.00271 AC XY: 365 AN XY: 134628

Gnomad AFR exome AF: 0.000685

Gnomad AMR exome AF: 0.00139

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000166

Gnomad FIN exome AF: 0.00371

Gnomad NFE exome AF: 0.00430

Gnomad OTH exome AF: 0.00280

GnomAD4 exome AF: 0.00361 AC: 5257 AN: 1457704 Hom.: 10 Cov.: 28 AF XY: 0.00357 AC XY: 2591 AN XY: 725310

Gnomad4 AFR exome AF: 0.000690

Gnomad4 AMR exome AF: 0.00136

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000163

Gnomad4 FIN exome AF: 0.00371

Gnomad4 NFE exome AF: 0.00433

Gnomad4 OTH exome AF: 0.00252

GnomAD4 genome AF: 0.00251 AC: 382 AN: 152346 Hom.: 2 Cov.: 33 AF XY: 0.00244 AC XY: 182 AN XY: 74500

Gnomad4 AFR AF: 0.000649

Gnomad4 AMR AF: 0.00124

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00424

Gnomad4 NFE AF: 0.00423

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.00392 Hom.: 1

Bravo AF: 0.00233

TwinsUK AF: 0.00431 AC: 16

ALSPAC AF: 0.00363 AC: 14

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00419 AC: 36

ExAC AF: 0.00272 AC: 330

EpiCase AF: 0.00475

EpiControl AF: 0.00369

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Nov 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NEK5: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	0.074
DANN	Benign	0.32
DEOGEN2	Benign	0.015	.;T;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.025	N
LIST_S2	Benign	0.47	T;.;T
M_CAP	Benign	0.0062	T
MetaRNN	Benign	0.0045	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.17	.;N;N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.46	.;N;.
REVEL	Benign	0.077
Sift	Benign	1.0	.;T;.
Sift4G	Benign	0.75	.;T;T
Polyphen		0.0	.;B;B
Vest4		0.036, 0.038
MVP		0.28
MPC		0.060
ClinPred		0.00080	T
GERP RS		-1.5
Varity_R		0.047
gMVP		0.038

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs149641412; hg19: chr13-52646203;