9-130681605-TCGCCGCCGCCGCCGCCGCCGCCGC-TCGCCGCCGC

Variant names:

• chr9-130681605-TCGCCGCCGCCGCCGC-T
• rs752427775
• NM_021619.3:c.1062_1076delCGCCGCCGCCGCCGC

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP3 BP6_Very_Strong BA1

The NM_021619.3(PRDM12):​c.1062_1076delCGCCGCCGCCGCCGC​(p.Ala355_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 0.00868 in 955,238 control chromosomes in the GnomAD database, including 335 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A354A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.016 (152 hom., cov: 0)
  • Exomes 𝑓: 0.0075 (183 hom.)
• Consequence: PRDM12 NM_021619.3 disruptive_inframe_deletion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• 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 -17 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_021619.3
• BP6: Variant 9-130681605-TCGCCGCCGCCGCCGC-T is Benign according to our data. Variant chr9-130681605-TCGCCGCCGCCGCCGC-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 475808.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.213 is higher than 0.05.

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.1062_1076delCGCCGCCGCCGCCGC	p.Ala355_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.1062_1076delCGCCGCCGCCGCCGC	p.Ala355_Ala359del	disruptive_inframe_deletion	Exon 5 of 5	ENSP00000253008.2	Q9H4Q4
	PRDM12	ENST00000676323.1		c.906+156_906+170delCGCCGCCGCCGCCGC		intron	N/A	ENSP00000502471.1	A0A6Q8PH01

Frequencies

GnomAD3 genomes AF: 0.0156 AC: 2214 AN: 141868 Hom.: 153 Cov.: 0

Gnomad AFR AF: 0.00265

Gnomad AMI AF: 0.00114

Gnomad AMR AF: 0.0282

Gnomad ASJ AF: 0.0134

Gnomad EAS AF: 0.225

Gnomad SAS AF: 0.0634

Gnomad FIN AF: 0.00422

Gnomad MID AF: 0.0137

Gnomad NFE AF: 0.00382

Gnomad OTH AF: 0.0129

GnomAD2 exomes AF: 0.00 AC: 0 AN: 16 AF XY: 0.00

Gnomad NFE exome AF: 0.00

GnomAD4 exome AF: 0.00748 AC: 6080 AN: 813332 Hom.: 183 AF XY: 0.00736 AC XY: 2776 AN XY: 377252

African (AFR) AF: 0.00250 AC: 37 AN: 14820

American (AMR) AF: 0.0157 AC: 20 AN: 1274

Ashkenazi Jewish (ASJ) AF: 0.00900 AC: 47 AN: 5224

East Asian (EAS) AF: 0.222 AC: 880 AN: 3958

South Asian (SAS) AF: 0.0618 AC: 1001 AN: 16208

European-Finnish (FIN) AF: 0.000699 AC: 1 AN: 1430

Middle Eastern (MID) AF: 0.00750 AC: 12 AN: 1600

European-Non Finnish (NFE) AF: 0.00464 AC: 3444 AN: 742054

Other (OTH) AF: 0.0238 AC: 638 AN: 26764

GnomAD4 genome AF: 0.0156 AC: 2213 AN: 141906 Hom.: 152 Cov.: 0 AF XY: 0.0178 AC XY: 1224 AN XY: 68750

African (AFR) AF: 0.00270 AC: 106 AN: 39292

American (AMR) AF: 0.0283 AC: 409 AN: 14470

Ashkenazi Jewish (ASJ) AF: 0.0134 AC: 45 AN: 3350

East Asian (EAS) AF: 0.224 AC: 1048 AN: 4678

South Asian (SAS) AF: 0.0639 AC: 294 AN: 4602

European-Finnish (FIN) AF: 0.00422 AC: 33 AN: 7820

Middle Eastern (MID) AF: 0.0150 AC: 4 AN: 266

European-Non Finnish (NFE) AF: 0.00382 AC: 247 AN: 64608

Other (OTH) AF: 0.0134 AC: 26 AN: 1944

Alfa AF: 0.00159 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	not provided (1)
-	-	1	not specified (1)
-	-	1	PRDM12-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.3
Mutation Taster		=192/8	polymorphism (auto)

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; COSMIC: COSV105872156;