Variant 8-6870793-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_005218.4(DEFB1):c.95C>G(p.Ser32Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000291 in 1,614,096 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000027 ( 0 hom. )

Consequence

DEFB1
NM_005218.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.47

Variant links:

Genes affected

DEFB1 (HGNC:2766): (defensin beta 1) Defensins form a family of microbicidal and cytotoxic peptides made by neutrophils. Members of the defensin family are highly similar in protein sequence. This gene encodes defensin, beta 1, an antimicrobial peptide implicated in the resistance of epithelial surfaces to microbial colonization. This gene maps in close proximity to defensin family member, defensin, alpha 1 and has been implicated in the pathogenesis of cystic fibrosis. [provided by RefSeq, Jul 2008]

DEFB1 links:

GS1-24F4.2 (HGNC:):

GS1-24F4.2 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.07798532).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DEFB1	NM_005218.4 linkuse as main transcript	c.95C>G	p.Ser32Cys	missense_variant	2/2	ENST00000297439.4	NP_005209.1	P60022

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
DEFB1	ENST00000297439.4 linkuse as main transcript	c.95C>G	p.Ser32Cys	missense_variant	2/2	1	NM_005218.4	ENSP00000297439.3	P60022
GS1-24F4.2	ENST00000531701.1 linkuse as main transcript	n.226-14329G>C		intron_variant		3
GS1-24F4.2	ENST00000655804.1 linkuse as main transcript	n.323-2388G>C		intron_variant

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152224

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00154

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000995

AC:

AN:

251268

Hom.:

AF XY:

0.0000663

AC XY:

AN XY:

135784

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00125

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000267

AC:

AN:

1461754

Hom.:

Cov.:

AF XY:

0.0000193

AC XY:

AN XY:

727154

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000831

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000525

AC:

AN:

152342

Hom.:

Cov.:

AF XY:

0.0000537

AC XY:

AN XY:

74486

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00154

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000604

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.0000659

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 03, 2023

The c.95C>G (p.S32C) alteration is located in exon 2 (coding exon 2) of the DEFB1 gene. This alteration results from a C to G substitution at nucleotide position 95, causing the serine (S) at amino acid position 32 to be replaced by a cysteine (C). 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

Pathogenic

0.83

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.36

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Uncertain

0.48

Eigen

Benign

-0.38

Eigen_PC

Benign

-0.57

FATHMM_MKL

Benign

0.15

M_CAP

Benign

0.0056

MetaRNN

Benign

0.078

MetaSVM

Benign

-1.0

PrimateAI

Benign

0.37

PROVEAN

Uncertain

-4.2

REVEL

Benign

0.12

Sift

Uncertain

0.0020

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.42

MutPred

0.41

Loss of disorder (P = 0.0022);

MVP

0.14

MPC

0.00027

ClinPred

0.23

GERP RS

-0.23

Varity_R

0.25

gMVP

0.15

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over