9-130681605-TCGCCGCCGCCGCCGCCGCCGCCGC-TCGCCGCCGCCGCCGCCGCCGCCGCCGCCGCCGCCGC

Variant names:

• chr9-130681605-T-TCGCCGCCGCCGC
• rs752427775
• NM_021619.3:c.1065_1076dupCGCCGCCGCCGC

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP3 BP6_Moderate BS1

The NM_021619.3(PRDM12):​c.1065_1076dupCGCCGCCGCCGC​(p.Ala356_Ala359dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Benign (★). Synonymous variant affecting the same amino acid position (i.e. A359A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00092 (0 hom., cov: 0)
  • Exomes 𝑓: 0.00020 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PRDM12 NM_021619.3 disruptive_inframe_insertion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 0.0910
• 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 -7 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_021619.3
• BP6: Variant 9-130681605-T-TCGCCGCCGCCGC is Benign according to our data. Variant chr9-130681605-T-TCGCCGCCGCCGC is described in ClinVar as Benign. ClinVar VariationId is 542463.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000916 (130/141914) while in subpopulation AFR AF = 0.00181 (71/39292). AF 95% confidence interval is 0.00147. There are 0 homozygotes in GnomAd4. There are 54 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.1065_1076dupCGCCGCCGCCGC	p.Ala356_Ala359dup	disruptive_inframe_insertion	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_1076dupCGCCGCCGCCGC	p.Ala356_Ala359dup	disruptive_inframe_insertion	Exon 5 of 5	ENSP00000253008.2	Q9H4Q4
	PRDM12	ENST00000676323.1		c.906+159_906+170dupCGCCGCCGCCGC		intron	N/A	ENSP00000502471.1	A0A6Q8PH01

Frequencies

GnomAD3 genomes AF: 0.000923 AC: 131 AN: 141874 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00184

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00124

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000426

Gnomad SAS AF: 0.00152

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00342

Gnomad NFE AF: 0.000480

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000197 AC: 160 AN: 813292 Hom.: 0 Cov.: 6 AF XY: 0.000186 AC XY: 70 AN XY: 377232

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000945 AC: 14 AN: 14816

American (AMR) AF: 0.00 AC: 0 AN: 1274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 5224

East Asian (EAS) AF: 0.000253 AC: 1 AN: 3958

South Asian (SAS) AF: 0.000308 AC: 5 AN: 16210

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: 0.000181 AC: 134 AN: 742018

Other (OTH) AF: 0.000187 AC: 5 AN: 26762

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000916 AC: 130 AN: 141914 Hom.: 0 Cov.: 0 AF XY: 0.000785 AC XY: 54 AN XY: 68752

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

American (AMR) AF: 0.00124 AC: 18 AN: 14470

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

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

South Asian (SAS) AF: 0.00152 AC: 7 AN: 4604

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 7820

Middle Eastern (MID) AF: 0.00376 AC: 1 AN: 266

European-Non Finnish (NFE) AF: 0.000480 AC: 31 AN: 64610

Other (OTH) AF: 0.00 AC: 0 AN: 1946

Alfa AF: 0.00 Hom.: 347

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	Congenital insensitivity to pain-hypohidrosis syndrome (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.091
Mutation Taster		=82/18	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;