8-11973965-G-C

Position:

• chr8-11973965-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001033018.2(DEFB136):​c.209C>G​(p.Pro70Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000207 in 1,449,796 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: DEFB136 NM_001033018.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.220

Genes affected

DEFB136 (HGNC:34433): (defensin beta 136) Defensins are cysteine-rich cationic polypeptides that are important in the immunologic response to invading microorganisms. The antimicrobial protein encoded by this gene is secreted and is a member of the beta defensin protein family. Beta defensin genes are found in several clusters throughout the genome, with this gene mapping to a cluster at 8p23. [provided by RefSeq, Nov 2014]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DEFB136	NM_001033018.2	c.209C>G	p.Pro70Arg	missense_variant	2/2	ENST00000382209.2	NP_001028190.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DEFB136	ENST00000382209.2	c.209C>G	p.Pro70Arg	missense_variant	2/2	1	NM_001033018.2	ENSP00000371644.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000207 AC: 3 AN: 1449796 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 720412

Gnomad4 AFR exome AF: 0.0000606

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.04e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 25, 2024

The c.209C>G (p.P70R) alteration is located in exon 2 (coding exon 2) of the DEFB136 gene. This alteration results from a C to G substitution at nucleotide position 209, causing the proline (P) at amino acid position 70 to be replaced by an arginine (R). 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	0.44
BayesDel_addAF	Benign	-0.062	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	15
DANN	Uncertain	0.99
DEOGEN2	Benign	0.21	T
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.65
FATHMM_MKL	Benign	0.047	N
M_CAP	Benign	0.0092	T
MetaRNN	Uncertain	0.50	D
MetaSVM	Benign	-0.97	T
PrimateAI	Benign	0.33	T
PROVEAN	Pathogenic	-8.4	D
REVEL	Benign	0.088
Sift	Uncertain	0.012	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.55
MutPred		0.27		Loss of loop (P = 0.0153);
MVP		0.030
MPC		0.43
ClinPred		0.62	D
GERP RS		1.3
Varity_R		0.17
gMVP		0.55

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: rs755111812; hg19: chr8-11831474;