9-130681605-TCGCCGCCGCCGCCGCCGCCGCCGC-TCGCCGCCGCCGCCGCCGC

Variant names:

• chr9-130681605-TCGCCGC-T
• rs752427775
• NM_021619.3:c.1071_1076delCGCCGC

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP3 BP6_Very_Strong BS1

The NM_021619.3(PRDM12):​c.1071_1076delCGCCGC​(p.Ala358_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 0.00124 in 955,000 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0022 (0 hom., cov: 0)
  • Exomes 𝑓: 0.0011 (0 hom.)
• Consequence: PRDM12 NM_021619.3 disruptive_inframe_deletion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.33
• Publications: 1 publications found

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 Gene-Disease associations (from GenCC):

• congenital insensitivity to pain-hypohidrosis syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet
• hereditary sensory and autonomic neuropathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: Illumina

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_021619.3
• BP6: Variant 9-130681605-TCGCCGC-T is Benign according to our data. Variant chr9-130681605-TCGCCGC-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 475811.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00221 (313/141912) while in subpopulation AMR AF = 0.00822 (119/14470). AF 95% confidence interval is 0.00702. There are 0 homozygotes in GnomAd4. There are 185 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021619.3. 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
	PRDM12	NM_021619.3	MANE Select	c.1071_1076delCGCCGC	p.Ala358_Ala359del	disruptive_inframe_deletion	Exon 5 of 5	NP_067632.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRDM12	ENST00000253008.3	TSL:1 MANE Select	c.1071_1076delCGCCGC	p.Ala358_Ala359del	disruptive_inframe_deletion	Exon 5 of 5	ENSP00000253008.2	Q9H4Q4
	PRDM12	ENST00000676323.1		c.906+165_906+170delCGCCGC		intron	N/A	ENSP00000502471.1	A0A6Q8PH01

Frequencies

GnomAD3 genomes AF: 0.00220 AC: 312 AN: 141872 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00181

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00816

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00384

Gnomad SAS AF: 0.00216

Gnomad FIN AF: 0.00192

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00122

Gnomad OTH AF: 0.000518

GnomAD4 exome AF: 0.00107 AC: 869 AN: 813088 Hom.: 0 AF XY: 0.00110 AC XY: 414 AN XY: 377132

African (AFR) AF: 0.00223 AC: 33 AN: 14818

American (AMR) AF: 0.00472 AC: 6 AN: 1272

Ashkenazi Jewish (ASJ) AF: 0.000191 AC: 1 AN: 5224

East Asian (EAS) AF: 0.00404 AC: 16 AN: 3956

South Asian (SAS) AF: 0.00315 AC: 51 AN: 16202

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 1430

Middle Eastern (MID) AF: 0.000625 AC: 1 AN: 1600

European-Non Finnish (NFE) AF: 0.000977 AC: 725 AN: 741832

Other (OTH) AF: 0.00135 AC: 36 AN: 26754

GnomAD4 genome AF: 0.00221 AC: 313 AN: 141912 Hom.: 0 Cov.: 0 AF XY: 0.00269 AC XY: 185 AN XY: 68752

African (AFR) AF: 0.00181 AC: 71 AN: 39292

American (AMR) AF: 0.00822 AC: 119 AN: 14470

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3350

East Asian (EAS) AF: 0.00385 AC: 18 AN: 4678

South Asian (SAS) AF: 0.00217 AC: 10 AN: 4604

European-Finnish (FIN) AF: 0.00192 AC: 15 AN: 7820

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 266

European-Non Finnish (NFE) AF: 0.00122 AC: 79 AN: 64610

Other (OTH) AF: 0.000514 AC: 1 AN: 1946

Alfa AF: 0.00 Hom.: 347

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Congenital insensitivity to pain-hypohidrosis syndrome (1)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.3
Mutation Taster		=173/27	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs752427775; hg19: chr9-133556992;