Variant 9-130681605-TCGCCGCCGCCGCCGCCGCCGCCGC-TCGCCGCCGCCGCCGCCGCCGCCGCCGCCGCCGCCGCCGCCGCCGC details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP3

The NM_021619.3(PRDM12):c.1056_1076dupCGCCGCCGCCGCCGCCGCCGC(p.Ala353_Ala359dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000049 ( 0 hom., cov: 0)

Exomes 𝑓: 0.000012 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

PRDM12
NM_021619.3 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.0910

Variant links:

Genes affected

PRDM12 (HGNC:13997): (PR/SET domain 12) This gene encodes a transcriptional regulator of sensory neuronal specification that plays a critical role in pain perception. The encoded protein contains an N-terminal PRDI-BF1 and RIZ homology (PR) domain, a SET domain, and three C-terminal C2H2 zinc finger DNA-binding domains. Naturally occurring mutations in this gene are associated with congenital insensitivity to pain (CIP), and hereditary sensory and autonomic neuropathies (HSAN's) affecting peripheral sensory and autonomic neurons. Deregulation of this gene is associated with solid cancers and hematological malignancies including chronic myeloid leukaemia. [provided by RefSeq, Mar 2017]

PRDM12 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_021619.3

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRDM12	NM_021619.3 link	c.1056_1076dupCGCCGCCGCCGCCGCCGCCGC	p.Ala353_Ala359dup	disruptive_inframe_insertion	Exon 5 of 5	ENST00000253008.3	NP_067632.2	Q9H4Q4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRDM12	ENST00000253008.3 link	c.1056_1076dupCGCCGCCGCCGCCGCCGCCGC	p.Ala353_Ala359dup	disruptive_inframe_insertion	Exon 5 of 5	1	NM_021619.3	ENSP00000253008.2		Q9H4Q4
PRDM12	ENST00000676323.1 link	c.906+150_906+170dupCGCCGCCGCCGCCGCCGCCGC		intron_variant	Intron 5 of 5			ENSP00000502471.1		A0A6Q8PH01

Frequencies

GnomAD3 genomes

AF:

0.0000493

AC:

AN:

141876

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000255

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000346

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000518

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000123

AC:

AN:

813334

Hom.:

Cov.:

AF XY:

0.0000133

AC XY:

AN XY:

377250

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000253

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000121

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000493

AC:

AN:

141916

Hom.:

Cov.:

AF XY:

0.0000582

AC XY:

AN XY:

68754

show subpopulations

Gnomad4 AFR

AF:

0.0000255

Gnomad4 AMR

AF:

0.000345

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000514

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Congenital insensitivity to pain-hypohidrosis syndrome

Uncertain:1

Jun 07, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, this variant is a rare in-frame duplication that has been shown to affect protein function. While it is absent from the population and reported in affected individuals, the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies have shown that this polyalanine expansion variant forms aggregates and reduces PRDM12 expression in vitro (PMID: 26005867). This variant has been reported to segregate with congenital insensitivity to pain in a single family (PMID: 26005867). This variant is not present in population databases (ExAC no frequency). This sequence change inserts 21 nucleotides in exon 5 of the PRDM12 mRNA (c.1056_1076dup). This leads to the insertion of 7 alanine amino acid residuer in the PRDM12 protein (p.Ala353_Ala359dup) but otherwise preserves the integrity of the reading frame. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over