rs669561

Variant names:

• chr16-4336813-T-C
• rs669561
• NM_032575.3:c.864T>C

Your query was ambiguous. Multiple possible variants found:

• chr16-4336813-T-C
• chr16-4336813-T-A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_032575.3(GLIS2):​c.864T>C​(p.Tyr288Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.972 in 1,613,022 control chromosomes in the GnomAD database, including 762,627 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.98 (73187 hom., cov: 34)
  • Exomes 𝑓: 0.97 (689440 hom.)
• Consequence: GLIS2 NM_032575.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.413
• Publications: 20 publications found

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]

PAM16 Gene-Disease associations (from GenCC):

• autosomal recessive spondylometaphyseal dysplasia, Megarbane type

  Inheritance: AR Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics

ENSG00000262712 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.6).
• BP6: Variant 16-4336813-T-C is Benign according to our data. Variant chr16-4336813-T-C is described in ClinVar as Benign. ClinVar VariationId is 96224.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.413 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.986 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032575.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLIS2	NM_032575.3	MANE Select	c.864T>C	p.Tyr288Tyr	synonymous	Exon 7 of 7	NP_115964.2	Q9BZE0
	GLIS2	NM_001318918.2		c.864T>C	p.Tyr288Tyr	synonymous	Exon 8 of 8	NP_001305847.1	Q9BZE0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLIS2	ENST00000433375.2	TSL:1 MANE Select	c.864T>C	p.Tyr288Tyr	synonymous	Exon 7 of 7	ENSP00000395547.1	Q9BZE0
	GLIS2	ENST00000886081.1		c.900T>C	p.Tyr300Tyr	synonymous	Exon 7 of 7	ENSP00000556140.1
	GLIS2	ENST00000927239.1		c.867T>C	p.Tyr289Tyr	synonymous	Exon 7 of 7	ENSP00000597298.1

Frequencies

GnomAD3 genomes AF: 0.980 AC: 149164 AN: 152178 Hom.: 73128 Cov.: 34

Gnomad AFR AF: 0.994

Gnomad AMI AF: 0.898

Gnomad AMR AF: 0.986

Gnomad ASJ AF: 0.992

Gnomad EAS AF: 0.999

Gnomad SAS AF: 0.989

Gnomad FIN AF: 0.975

Gnomad MID AF: 0.981

Gnomad NFE AF: 0.969

Gnomad OTH AF: 0.982

GnomAD2 exomes AF: 0.980 AC: 244329 AN: 249380 AF XY: 0.979

Gnomad AFR exome AF: 0.995

Gnomad AMR exome AF: 0.989

Gnomad ASJ exome AF: 0.993

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 0.974

Gnomad NFE exome AF: 0.969

Gnomad OTH exome AF: 0.978

GnomAD4 exome AF: 0.972 AC: 1419140 AN: 1460726 Hom.: 689440 Cov.: 71 AF XY: 0.972 AC XY: 706507 AN XY: 726648

African (AFR) AF: 0.996 AC: 33361 AN: 33480

American (AMR) AF: 0.988 AC: 44179 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.993 AC: 25948 AN: 26134

East Asian (EAS) AF: 1.00 AC: 39696 AN: 39698

South Asian (SAS) AF: 0.989 AC: 85338 AN: 86254

European-Finnish (FIN) AF: 0.973 AC: 50953 AN: 52356

Middle Eastern (MID) AF: 0.982 AC: 5662 AN: 5768

European-Non Finnish (NFE) AF: 0.967 AC: 1075146 AN: 1111954

Other (OTH) AF: 0.975 AC: 58857 AN: 60384

GnomAD4 genome AF: 0.980 AC: 149282 AN: 152296 Hom.: 73187 Cov.: 34 AF XY: 0.980 AC XY: 72987 AN XY: 74466

African (AFR) AF: 0.994 AC: 41332 AN: 41564

American (AMR) AF: 0.986 AC: 15087 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.992 AC: 3443 AN: 3472

East Asian (EAS) AF: 0.999 AC: 5175 AN: 5178

South Asian (SAS) AF: 0.989 AC: 4775 AN: 4830

European-Finnish (FIN) AF: 0.975 AC: 10368 AN: 10630

Middle Eastern (MID) AF: 0.980 AC: 288 AN: 294

European-Non Finnish (NFE) AF: 0.969 AC: 65918 AN: 68008

Other (OTH) AF: 0.982 AC: 2077 AN: 2114

Alfa AF: 0.975 Hom.: 113111

Bravo AF: 0.981

Asia WGS AF: 0.992 AC: 3450 AN: 3478

EpiCase AF: 0.974

EpiControl AF: 0.971

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	Nephronophthisis 7 (2)
-	-	2	not provided (2)
-	-	1	Nephronophthisis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
CADD	Benign	4.9
DANN	Benign	0.57
PhyloP100		-0.41
Mutation Taster		=96/4	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs669561; hg19: chr16-4386814; COSMIC: COSV52111438; COSMIC: COSV52111438;