chr9-13107002-C-T

Variant names:

• chr9-13107002-C-T
• rs193280665
• NM_001378778.1:c.6176G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001378778.1(MPDZ):​c.6176G>A​(p.Arg2059Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00086 in 1,613,532 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2059W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0047 (5 hom., cov: 32)
  • Exomes 𝑓: 0.00046 (3 hom.)
• Consequence: MPDZ NM_001378778.1 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 3.69
• Publications: 5 publications found

Genes affected

MPDZ (HGNC:7208): (multiple PDZ domain crumbs cell polarity complex component) The protein encoded by this gene has multiple PDZ domains, which are hallmarks of protein-protein interactions. The encoded protein is known to interact with the HTR2C receptor and may cause it to clump at the cell surface. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2015]

MPDZ Gene-Disease associations (from GenCC):

• hydrocephalus, nonsyndromic, autosomal recessive 2

  Inheritance: AR Classification: STRONG, MODERATE, LIMITED Submitted by: Laboratory for Molecular Medicine, Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, G2P

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009553522).
• BP6: Variant 9-13107002-C-T is Benign according to our data. Variant chr9-13107002-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 791296.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0047 (715/152234) while in subpopulation AFR AF = 0.0162 (673/41538). AF 95% confidence interval is 0.0152. There are 5 homozygotes in GnomAd4. There are 340 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001378778.1. 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
	MPDZ	NM_001378778.1	MANE Select	c.6176G>A	p.Arg2059Gln	missense	Exon 47 of 47	NP_001365707.1	O75970-1
	MPDZ	NM_001375413.1		c.6275G>A	p.Arg2092Gln	missense	Exon 48 of 48	NP_001362342.1
	MPDZ	NM_001330637.2		c.6176G>A	p.Arg2059Gln	missense	Exon 47 of 47	NP_001317566.1	O75970-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MPDZ	ENST00000319217.12	TSL:5 MANE Select	c.6176G>A	p.Arg2059Gln	missense	Exon 47 of 47	ENSP00000320006.7	O75970-1
	MPDZ	ENST00000541718.5	TSL:1	c.6089G>A	p.Arg2030Gln	missense	Exon 46 of 46	ENSP00000439807.1	O75970-2
	MPDZ	ENST00000447879.6	TSL:1	c.6077G>A	p.Arg2026Gln	missense	Exon 46 of 46	ENSP00000415208.1	O75970-3

Frequencies

GnomAD3 genomes AF: 0.00471 AC: 717 AN: 152116 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.0163

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00151

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00671

GnomAD2 exomes AF: 0.00123 AC: 307 AN: 249260 AF XY: 0.000895

Gnomad AFR exome AF: 0.0178

Gnomad AMR exome AF: 0.000550

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000796

Gnomad OTH exome AF: 0.000330

GnomAD4 exome AF: 0.000460 AC: 672 AN: 1461298 Hom.: 3 Cov.: 30 AF XY: 0.000391 AC XY: 284 AN XY: 726970

African (AFR) AF: 0.0166 AC: 555 AN: 33472

American (AMR) AF: 0.000626 AC: 28 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26116

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.0000696 AC: 6 AN: 86222

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53392

Middle Eastern (MID) AF: 0.000693 AC: 4 AN: 5768

European-Non Finnish (NFE) AF: 0.0000297 AC: 33 AN: 1111560

Other (OTH) AF: 0.000762 AC: 46 AN: 60350

GnomAD4 genome AF: 0.00470 AC: 715 AN: 152234 Hom.: 5 Cov.: 32 AF XY: 0.00457 AC XY: 340 AN XY: 74430

African (AFR) AF: 0.0162 AC: 673 AN: 41538

American (AMR) AF: 0.00150 AC: 23 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68020

Other (OTH) AF: 0.00664 AC: 14 AN: 2108

Alfa AF: 0.00156 Hom.: 5

Bravo AF: 0.00513

ESP6500AA AF: 0.0165 AC: 66

ESP6500EA AF: 0.000120 AC: 1

ExAC AF: 0.00151 AC: 182

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Hydrocephalus, nonsyndromic, autosomal recessive 2 (1)
-	-	1	MPDZ-related disorder (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.50
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.039	T
Eigen	Uncertain	0.20
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.89	D
MetaRNN	Benign	0.0096	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.28	N
PhyloP100		3.7
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.13
Sift	Benign	0.21	T
Sift4G	Benign	0.15	T
Polyphen		0.95	P
Vest4		0.28
MVP		0.36
ClinPred		0.030	T
GERP RS		4.6
Varity_R		0.33
gMVP		0.23
Mutation Taster		=89/11	polymorphism

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

Other links and lift over

dbSNP: rs193280665; hg19: chr9-13107001;