20-23421338-T-C

Position:

• chr20-23421338-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The ENST00000377026.4(NAPB):​c.65A>G​(p.Lys22Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0017 in 1,565,400 control chromosomes in the GnomAD database, including 56 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0020 (4 hom., cov: 34)
  • Exomes 𝑓: 0.0017 (52 hom.)
• Consequence: NAPB ENST00000377026.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 2.89

Genes affected

NAPB (HGNC:15751): (NSF attachment protein beta) This gene encodes a member of the soluble N-ethyl-maleimide-sensitive fusion attachment protein (SNAP) family. SNAP proteins play a critical role in the docking and fusion of vesicles to target membranes as part of the 20S NSF-SNAP-SNARE complex. This gene encodes the SNAP beta isoform which has been shown to be preferentially expressed in brain tissue. The encoded protein also interacts with the GluR2 α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptor subunit C-terminus and may play a role as a chaperone in the molecular processing of the AMPA receptor. [provided by RefSeq, Mar 2017]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0030188859).
• BP6: Variant 20-23421338-T-C is Benign according to our data. Variant chr20-23421338-T-C is described in ClinVar as [Benign]. Clinvar id is 709378.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.002 (304/152262) while in subpopulation EAS AF= 0.0463 (239/5160). AF 95% confidence interval is 0.0415. There are 4 homozygotes in gnomad4. There are 165 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NAPB	NM_022080.3	c.65A>G	p.Lys22Arg	missense_variant	1/11	ENST00000377026.4	NP_071363.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NAPB	ENST00000377026.4	c.65A>G	p.Lys22Arg	missense_variant	1/11	1	NM_022080.3	ENSP00000366225	P3

Frequencies

GnomAD3 genomes AF: 0.00200 AC: 305 AN: 152144 Hom.: 4 Cov.: 34

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00177

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0464

Gnomad SAS AF: 0.000620

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000294

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00439 AC: 769 AN: 175204 Hom.: 16 AF XY: 0.00409 AC XY: 385 AN XY: 94018

Gnomad AFR exome AF: 0.0000971

Gnomad AMR exome AF: 0.00461

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0451

Gnomad SAS exome AF: 0.000787

Gnomad FIN exome AF: 0.000796

Gnomad NFE exome AF: 0.000255

Gnomad OTH exome AF: 0.00152

GnomAD4 exome AF: 0.00167 AC: 2360 AN: 1413138 Hom.: 52 Cov.: 32 AF XY: 0.00155 AC XY: 1082 AN XY: 699042

Gnomad4 AFR exome AF: 0.0000627

Gnomad4 AMR exome AF: 0.00412

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0500

Gnomad4 SAS exome AF: 0.000671

Gnomad4 FIN exome AF: 0.000465

Gnomad4 NFE exome AF: 0.000184

Gnomad4 OTH exome AF: 0.00161

GnomAD4 genome AF: 0.00200 AC: 304 AN: 152262 Hom.: 4 Cov.: 34 AF XY: 0.00222 AC XY: 165 AN XY: 74454

Gnomad4 AFR AF: 0.000168

Gnomad4 AMR AF: 0.00176

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0463

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.000282

Gnomad4 NFE AF: 0.000294

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00220 Hom.: 20

Bravo AF: 0.00249

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000235 AC: 2

ExAC AF: 0.00328 AC: 384

Asia WGS AF: 0.0130 AC: 45 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

NAPB-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 30, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 04, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.34
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.16	.;.;T
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.071
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.85	D;D;D
MetaRNN	Benign	0.0030	T;T;T
MetaSVM	Benign	-0.70	T
MutationAssessor	Benign	1.9	L;.;L
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-1.1	N;.;N
REVEL	Uncertain	0.30
Sift	Benign	0.11	T;.;T
Sift4G	Benign	0.083	T;T;T
Polyphen		0.010	.;.;B
Vest4		0.25
MVP		0.69
MPC		0.68
ClinPred		0.012	T
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.24
gMVP		0.36

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

Publications

LitVar

Other links and lift over

dbSNP: rs140977227; hg19: chr20-23401975; COSMIC: COSV65464209;