9-130681605-TCGCCGCCGCCGCCGCCGCCGCCGC-TCGCCGCCGCCGC

Variant names:

• chr9-130681605-TCGCCGCCGCCGC-T
• rs752427775
• NM_021619.3:c.1065_1076delCGCCGCCGCCGC

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.1065_1076delCGCCGCCGCCGC​(p.Ala356_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 0.000466 in 954,886 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. A355A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00066 (0 hom., cov: 0)
  • Exomes 𝑓: 0.00043 (0 hom.)
• Consequence: PRDM12 NM_021619.3 disruptive_inframe_deletion
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• 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-TCGCCGCCGCCGC-T is Benign according to our data. Variant chr9-130681605-TCGCCGCCGCCGC-T is described in ClinVar as Likely_benign. ClinVar VariationId is 542462.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.000433 (352/812972) while in subpopulation MID AF = 0.00187 (3/1600). AF 95% confidence interval is 0.00057. There are 0 homozygotes in GnomAdExome4. There are 160 alleles in the male GnomAdExome4 subpopulation. 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.1065_1076delCGCCGCCGCCGC	p.Ala356_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.1065_1076delCGCCGCCGCCGC	p.Ala356_Ala359del	disruptive_inframe_deletion	Exon 5 of 5	ENSP00000253008.2	Q9H4Q4
	PRDM12	ENST00000676323.1		c.906+159_906+170delCGCCGCCGCCGC		intron	N/A	ENSP00000502471.1	A0A6Q8PH01

Frequencies

GnomAD3 genomes AF: 0.000656 AC: 93 AN: 141874 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000663

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000622

Gnomad ASJ AF: 0.00119

Gnomad EAS AF: 0.000426

Gnomad SAS AF: 0.000866

Gnomad FIN AF: 0.000895

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000604

Gnomad OTH AF: 0.00104

GnomAD4 exome AF: 0.000433 AC: 352 AN: 812972 Hom.: 0 AF XY: 0.000424 AC XY: 160 AN XY: 377090

African (AFR) AF: 0.000675 AC: 10 AN: 14818

American (AMR) AF: 0.000785 AC: 1 AN: 1274

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 6 AN: 5224

East Asian (EAS) AF: 0.000505 AC: 2 AN: 3958

South Asian (SAS) AF: 0.000925 AC: 15 AN: 16210

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

Middle Eastern (MID) AF: 0.00187 AC: 3 AN: 1600

European-Non Finnish (NFE) AF: 0.000403 AC: 299 AN: 741700

Other (OTH) AF: 0.000598 AC: 16 AN: 26758

GnomAD4 genome AF: 0.000655 AC: 93 AN: 141914 Hom.: 0 Cov.: 0 AF XY: 0.000655 AC XY: 45 AN XY: 68752

African (AFR) AF: 0.000662 AC: 26 AN: 39290

American (AMR) AF: 0.000622 AC: 9 AN: 14472

Ashkenazi Jewish (ASJ) AF: 0.00119 AC: 4 AN: 3350

East Asian (EAS) AF: 0.000427 AC: 2 AN: 4680

South Asian (SAS) AF: 0.000869 AC: 4 AN: 4604

European-Finnish (FIN) AF: 0.000895 AC: 7 AN: 7820

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

European-Non Finnish (NFE) AF: 0.000604 AC: 39 AN: 64610

Other (OTH) AF: 0.00103 AC: 2 AN: 1946

Alfa AF: 0.00 Hom.: 347

ClinVar

ClinVar submissions

Significance: 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)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.3
Mutation Taster		=191/9	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;