NM_016580.4:c.3516C>A

Variant names:

• chr5-141945420-G-T
• rs747203199
• NM_016580.4:c.3516C>A

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BS1 BS2

The NM_016580.4(PCDH12):​c.3516C>A​(p.Gly1172Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000647 in 1,498,960 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000093 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000062 (2 hom.)
• Consequence: PCDH12 NM_016580.4 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.899
• Publications: 0 publications found

Genes affected

PCDH12 (HGNC:8657): (protocadherin 12) This gene belongs to the protocadherin gene family, a subfamily of the cadherin superfamily. The encoded protein consists of an extracellular domain containing 6 cadherin repeats, a transmembrane domain and a cytoplasmic tail that differs from those of the classical cadherins. The gene localizes to the region on chromosome 5 where the protocadherin gene clusters reside. The exon organization of this transcript is similar to that of the gene cluster transcripts, notably the first large exon, but no significant sequence homology exists. The function of this cellular adhesion protein is undetermined but mouse protocadherin 12 does not bind catenins and appears to have no affect on cell migration or growth. [provided by RefSeq, Jul 2008]

DELE1 (HGNC:28969): (DAP3 binding cell death enhancer 1) Enables protein kinase binding activity and protein serine/threonine kinase activator activity. Involved in HRI-mediated signaling; extrinsic apoptotic signaling pathway via death domain receptors; and regulation of cysteine-type endopeptidase activity involved in apoptotic process. Located in cytosol and mitochondrial inner membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Benign. The variant received -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 5-141945420-G-T is Benign according to our data. Variant chr5-141945420-G-T is described in ClinVar as Likely_benign. ClinVar VariationId is 2889160.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.899 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0000929 (13/139962) while in subpopulation AMR AF = 0.000524 (7/13354). AF 95% confidence interval is 0.000245. There are 0 homozygotes in GnomAd4. There are 8 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016580.4. 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
	PCDH12	NM_016580.4	MANE Select	c.3516C>A	p.Gly1172Gly	synonymous	Exon 4 of 4	NP_057664.1	Q9NPG4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCDH12	ENST00000231484.4	TSL:1 MANE Select	c.3516C>A	p.Gly1172Gly	synonymous	Exon 4 of 4	ENSP00000231484.3	Q9NPG4
	DELE1	ENST00000895929.1		c.*2-1380G>T		intron	N/A	ENSP00000565988.1

Frequencies

GnomAD3 genomes AF: 0.0000929 AC: 13 AN: 139876 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000524

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000243

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0103

Gnomad NFE AF: 0.0000158

Gnomad OTH AF: 0.000522

GnomAD2 exomes AF: 0.0000290 AC: 7 AN: 241572 AF XY: 0.0000535

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000586

Gnomad ASJ exome AF: 0.000101

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000280

Gnomad OTH exome AF: 0.000169

GnomAD4 exome AF: 0.0000618 AC: 84 AN: 1358998 Hom.: 2 Cov.: 64 AF XY: 0.0000578 AC XY: 39 AN XY: 674922

African (AFR) AF: 0.00 AC: 0 AN: 32104

American (AMR) AF: 0.0000802 AC: 3 AN: 37402

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24648

East Asian (EAS) AF: 0.00 AC: 0 AN: 35512

South Asian (SAS) AF: 0.0000128 AC: 1 AN: 78086

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51338

Middle Eastern (MID) AF: 0.00856 AC: 45 AN: 5258

European-Non Finnish (NFE) AF: 0.0000250 AC: 26 AN: 1037972

Other (OTH) AF: 0.000159 AC: 9 AN: 56678

GnomAD4 genome AF: 0.0000929 AC: 13 AN: 139962 Hom.: 0 Cov.: 33 AF XY: 0.000118 AC XY: 8 AN XY: 67840

African (AFR) AF: 0.00 AC: 0 AN: 39064

American (AMR) AF: 0.000524 AC: 7 AN: 13354

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3234

East Asian (EAS) AF: 0.00 AC: 0 AN: 4142

South Asian (SAS) AF: 0.000243 AC: 1 AN: 4108

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9524

Middle Eastern (MID) AF: 0.0112 AC: 3 AN: 268

European-Non Finnish (NFE) AF: 0.0000158 AC: 1 AN: 63458

Other (OTH) AF: 0.000515 AC: 1 AN: 1940

Alfa AF: 0.0000678 Hom.: 0

Bravo AF: 0.0000302

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	2.3
DANN	Benign	0.61
PhyloP100		0.90
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs747203199; hg19: chr5-141324985;