2-71068606-C-T

Variant names:

• chr2-71068606-C-T
• rs372401395
• ENST00000455662.6:c.61C>T

Variant summary

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

The ENST00000455662.6(NAGK):​c.61C>T​(p.Pro21Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000729 in 1,371,654 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P21A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.3e-7 (0 hom.)
• Consequence: NAGK ENST00000455662.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.13
• Publications: 0 publications found

Genes affected

NAGK (HGNC:17174): (N-acetylglucosamine kinase) This gene encodes a member of the N-acetylhexosamine kinase family. The encoded protein catalyzes the conversion of N-acetyl-D-glucosamine to N-acetyl-D-glucosamine 6-phosphate, and is the major mammalian enzyme which recovers amino sugars. [provided by RefSeq, Nov 2011]

ENSG00000272735 (HGNC:):

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=0.10965955).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000455662.6. 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
	NAGK	NM_001330426.2		c.-125+270C>T		intron	N/A	NP_001317355.1	C9JEV6
	NAGK	NM_017567.6	MANE Select	c.-78C>T		upstream_gene	N/A	NP_060037.4
	NAGK	NM_001330425.3		c.-146C>T		upstream_gene	N/A	NP_001317354.1	C9JEV6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NAGK	ENST00000455662.6	TSL:1	c.61C>T	p.Pro21Ser	missense	Exon 1 of 10	ENSP00000389087.2	Q9UJ70-2
	NAGK	ENST00000613852.4	TSL:1	c.61C>T	p.Pro21Ser	missense	Exon 1 of 10	ENSP00000477639.1	Q9UJ70-2
	NAGK	ENST00000868350.1		c.-78C>T		5_prime_UTR	Exon 1 of 10	ENSP00000538409.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.29e-7 AC: 1 AN: 1371654 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 676552

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

African (AFR) AF: 0.0000349 AC: 1 AN: 28668

American (AMR) AF: 0.00 AC: 0 AN: 31296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24190

East Asian (EAS) AF: 0.00 AC: 0 AN: 31982

South Asian (SAS) AF: 0.00 AC: 0 AN: 77478

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48850

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4764

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1067712

Other (OTH) AF: 0.00 AC: 0 AN: 56714

⚠️ 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.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.084	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	17
DANN	Benign	0.93
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.24
FATHMM_MKL	Benign	0.57	D
LIST_S2	Benign	0.41	T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-1.0	T
PhyloP100		3.1
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	0.020	N
REVEL	Benign	0.050
Sift	Pathogenic	0.0	D
Vest4		0.14
MutPred		0.21		Loss of loop (P = 0.0112)
MVP		0.17
MPC		0.24
ClinPred		0.51	D
GERP RS		3.8
PromoterAI		-0.11	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
gMVP		0.38
Mutation Taster		=91/9	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs372401395; hg19: chr2-71295736; COSMIC: COSV99730705; COSMIC: COSV99730705;