rs34543395

chr16-4332350-C-Achr16-4332350-C-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Moderate BP6_Very_Strong BP7 BS2

The NM_032575.3(GLIS2):c.70C>A(p.Arg24=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0111 in 1,613,142 control chromosomes in the GnomAD database, including 116 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0082 (14 hom., cov: 32)
  • Exomes 𝑓: 0.011 (102 hom.)
• Consequence: GLIS2 NM_032575.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.927

Genes affected

GLIS2 (HGNC:29450): (GLIS family zinc finger 2) This gene is a member of the GLI-similar zinc finger protein family and encodes a nuclear transcription factor with five C2H2-type zinc finger domains. The protein encoded by this gene is widely expressed at low levels in the neural tube and peripheral nervous system and likely promotes neuronal differentiation. It is abundantly expressed in the kidney and may have a role in the regulation of kidney morphogenesis. p120 regulates the expression level of this protein and induces the cleavage of this protein's C-terminal zinc finger domain. This protein also promotes the nuclear translocation of p120. Mutations in this gene cause nephronophthisis (NPHP), an autosomal recessive kidney disease characterized by tubular basement membrane disruption, interstitial lymphohistiocytic cell infiltration, and development of cysts at the corticomedullary border of the kidneys.[provided by RefSeq, Jan 2010]

PAM16 (HGNC:29679): (presequence translocase associated motor 16) This gene encodes a mitochondrial protein involved in granulocyte-macrophage colony-stimulating factor (GM-CSF) signaling. This protein also plays a role in the import of nuclear-encoded mitochondrial proteins into the mitochondrial matrix and may be important in reactive oxygen species (ROS) homeostasis. Mutations in this gene cause Megarbane-Dagher-Melike type spondylometaphyseal dysplasia, an early lethal skeletal dysplasia characterized by short stature, developmental delay and other skeletal abnormalities. [provided by RefSeq, May 2017]

ACMG classification

Verdict is Benign. Variant got -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.32).
• BP6: Variant 16-4332350-C-A is Benign according to our data. Variant chr16-4332350-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 215539.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-4332350-C-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.927 with no splicing effect.
• BS2: High Homozygotes in GnomAd at 14 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GLIS2	NM_032575.3	c.70C>A	p.Arg24=	synonymous_variant	2/7	ENST00000433375.2
GLIS2	NM_001318918.2	c.70C>A	p.Arg24=	synonymous_variant	3/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GLIS2	ENST00000433375.2	c.70C>A	p.Arg24=	synonymous_variant	2/7	1	NM_032575.3	P1
GLIS2	ENST00000262366.7	c.70C>A	p.Arg24=	synonymous_variant	3/8	2		P1
PAM16	ENST00000577031.5	c.292-576G>T		intron_variant		4

Frequencies

GnomAD3 genomes AF: 0.00817 AC: 1243 AN: 152212 Hom.: 14 Cov.: 32

Gnomad AFR AF: 0.00236

Gnomad AMI AF: 0.0899

Gnomad AMR AF: 0.00661

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.00574

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0129

Gnomad OTH AF: 0.00430

GnomAD3 exomes AF: 0.00656 AC: 1634 AN: 248986 Hom.: 13 AF XY: 0.00653 AC XY: 883 AN XY: 135238

Gnomad AFR exome AF: 0.00187

Gnomad AMR exome AF: 0.00365

Gnomad ASJ exome AF: 0.00210

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00183

Gnomad FIN exome AF: 0.00560

Gnomad NFE exome AF: 0.0110

Gnomad OTH exome AF: 0.00773

GnomAD4 exome AF: 0.0114 AC: 16600 AN: 1460812 Hom.: 102 Cov.: 32 AF XY: 0.0108 AC XY: 7869 AN XY: 726708

Gnomad4 AFR exome AF: 0.00140

Gnomad4 AMR exome AF: 0.00338

Gnomad4 ASJ exome AF: 0.00180

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00155

Gnomad4 FIN exome AF: 0.00637

Gnomad4 NFE exome AF: 0.0137

Gnomad4 OTH exome AF: 0.0110

GnomAD4 genome AF: 0.00816 AC: 1243 AN: 152330 Hom.: 14 Cov.: 32 AF XY: 0.00796 AC XY: 593 AN XY: 74486

Gnomad4 AFR AF: 0.00236

Gnomad4 AMR AF: 0.00660

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00574

Gnomad4 NFE AF: 0.0129

Gnomad4 OTH AF: 0.00426

Alfa AF: 0.00729 Hom.: 3

Bravo AF: 0.00791

Asia WGS AF: 0.000577 AC: 3 AN: 3478

EpiCase AF: 0.0105

EpiControl AF: 0.00984

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 30, 2017	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	GLIS2: BP4, BP7, BS1, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 03, 2020	- -

Nephronophthisis Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Nephronophthisis 7 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.32
Cadd	Benign	9.0
Dann	Benign	0.83
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs34543395; hg19: chr16-4382351;