9-130681605-TCGCCGCCGCCGCCGCCGCCGCCGC-TCGCCGC

Variant names:

• chr9-130681605-TCGCCGCCGCCGCCGCCGC-T
• rs752427775
• NM_021619.3:c.1059_1076delCGCCGCCGCCGCCGCCGC

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP3 BP6_Very_Strong BS1 BS2

The NM_021619.3(PRDM12):​c.1059_1076delCGCCGCCGCCGCCGCCGC​(p.Ala354_Ala359del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0104 in 955,234 control chromosomes in the GnomAD database, including 53 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0078 (7 hom., cov: 0)
  • Exomes 𝑓: 0.011 (46 hom.)
• Consequence: PRDM12 NM_021619.3 disruptive_inframe_deletion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.33

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]

ACMG classification

Our verdict: Benign. The variant received -17 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_021619.3
• BP6: Variant 9-130681605-TCGCCGCCGCCGCCGCCGC-T is Benign according to our data. Variant chr9-130681605-TCGCCGCCGCCGCCGCCGC-T is described in ClinVar as [Likely_benign]. Clinvar id is 475807.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-130681605-TCGCCGCCGCCGCCGCCGC-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00778 (1104/141912) while in subpopulation NFE AF = 0.012 (773/64610). AF 95% confidence interval is 0.0113. There are 7 homozygotes in GnomAd4. There are 521 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position FAILED quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRDM12	NM_021619.3	c.1059_1076delCGCCGCCGCCGCCGCCGC	p.Ala354_Ala359del	disruptive_inframe_deletion	Exon 5 of 5	ENST00000253008.3	NP_067632.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRDM12	ENST00000253008.3	c.1059_1076delCGCCGCCGCCGCCGCCGC	p.Ala354_Ala359del	disruptive_inframe_deletion	Exon 5 of 5	1	NM_021619.3	ENSP00000253008.2
PRDM12	ENST00000676323.1	c.906+153_906+170delCGCCGCCGCCGCCGCCGC		intron_variant	Intron 5 of 5			ENSP00000502471.1

Frequencies

GnomAD3 genomes AF: 0.00777 AC: 1103 AN: 141872 Hom.: 7 Cov.: 0

Gnomad AFR AF: 0.00311

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00588

Gnomad ASJ AF: 0.0179

Gnomad EAS AF: 0.000426

Gnomad SAS AF: 0.00238

Gnomad FIN AF: 0.00435

Gnomad MID AF: 0.0103

Gnomad NFE AF: 0.0120

Gnomad OTH AF: 0.00674

GnomAD2 exomes AF: 0.0625 AC: 1 AN: 16 AF XY: 0.125

Gnomad NFE exome AF: 0.0625

GnomAD4 exome AF: 0.0108 AC: 8787 AN: 813322 Hom.: 46 AF XY: 0.0109 AC XY: 4126 AN XY: 377244

Gnomad4 AFR exome AF: 0.00304 AC: 45 AN: 14820

Gnomad4 AMR exome AF: 0.00549 AC: 7 AN: 1274

Gnomad4 ASJ exome AF: 0.0178 AC: 93 AN: 5224

Gnomad4 EAS exome AF: 0.000253 AC: 1 AN: 3952

Gnomad4 SAS exome AF: 0.00228 AC: 37 AN: 16206

Gnomad4 FIN exome AF: 0.00140 AC: 2 AN: 1430

Gnomad4 NFE exome AF: 0.0112 AC: 8298 AN: 742058

Gnomad4 Remaining exome AF: 0.0107 AC: 287 AN: 26758

GnomAD4 genome AF: 0.00778 AC: 1104 AN: 141912 Hom.: 7 Cov.: 0 AF XY: 0.00758 AC XY: 521 AN XY: 68750

Gnomad4 AFR AF: 0.00313 AC: 0.00313041 AN: 0.00313041

Gnomad4 AMR AF: 0.00587 AC: 0.00587341 AN: 0.00587341

Gnomad4 ASJ AF: 0.0179 AC: 0.0179104 AN: 0.0179104

Gnomad4 EAS AF: 0.000427 AC: 0.00042735 AN: 0.00042735

Gnomad4 SAS AF: 0.00261 AC: 0.00260643 AN: 0.00260643

Gnomad4 FIN AF: 0.00435 AC: 0.00434894 AN: 0.00434894

Gnomad4 NFE AF: 0.0120 AC: 0.0119641 AN: 0.0119641

Gnomad4 OTH AF: 0.00669 AC: 0.00668724 AN: 0.00668724

Alfa AF: 0.00318 Hom.: 347

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Nov 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PRDM12: BS1, BS2 -

Nov 02, 2019

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Congenital insensitivity to pain-hypohidrosis syndrome Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Mutation Taster		=191/9	polymorphism

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs752427775; hg19: chr9-133556992;