chr17-36545769-C-A

Variant names:

• chr17-36545769-C-A
• rs140693226
• NM_024835.5:c.45C>A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_024835.5(GGNBP2):​c.45C>A​(p.Phe15Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000838 in 1,431,486 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000084 (0 hom.)
• Consequence: GGNBP2 NM_024835.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.26

Genes affected

GGNBP2 (HGNC:19357): (gametogenetin binding protein 2) Predicted to be involved in spermatogenesis. Predicted to act upstream of or within several processes, including labyrinthine layer blood vessel development; negative regulation of cell population proliferation; and negative regulation of protein phosphorylation. Predicted to be located in cytoplasmic vesicle. Predicted to be active in cytoplasm and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.028270274).
• BS2: High AC in GnomAdExome4 at 12 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GGNBP2	NM_024835.5	c.45C>A	p.Phe15Leu	missense_variant	Exon 2 of 14	ENST00000613102.5	NP_079111.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GGNBP2	ENST00000613102.5	c.45C>A	p.Phe15Leu	missense_variant	Exon 2 of 14	1	NM_024835.5	ENSP00000478220.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000506 AC: 10 AN: 197724 Hom.: 0 AF XY: 0.0000469 AC XY: 5 AN XY: 106684

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000339

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000838 AC: 12 AN: 1431486 Hom.: 0 Cov.: 30 AF XY: 0.00000705 AC XY: 5 AN XY: 709542

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000297

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000227

ExAC AF: 0.0000335 AC: 4

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 04, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.45C>A (p.F15L) alteration is located in exon 2 (coding exon 1) of the GGNBP2 gene. This alteration results from a C to A substitution at nucleotide position 45, causing the phenylalanine (F) at amino acid position 15 to be replaced by a leucine (L). 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	0.98
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.23
CADD	Uncertain	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.038	T;.;.
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.073
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.028	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	L;.;.
PrimateAI	Pathogenic	0.87	D
Sift4G	Benign	0.53	T;D;T
Polyphen		0.048	B;.;.
Vest4		0.42
MutPred		0.18		Gain of disorder (P = 0.1736);Gain of disorder (P = 0.1736);Gain of disorder (P = 0.1736);
MVP		0.043
ClinPred		0.20	T
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.44
gMVP		0.45

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: rs140693226; hg19: chr17-34901618;