5-102960019-C-T

Variant names:

• chr5-102960019-C-T
• rs2217252
• NM_001177306.2:c.1050C>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Moderate BP6_Moderate BP7 BS2

The NM_001177306.2(PAM):​c.1050C>T​(p.Pro350Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0109 in 1,610,326 control chromosomes in the GnomAD database, including 118 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0067 (8 hom., cov: 32)
  • Exomes 𝑓: 0.011 (110 hom.)
• Consequence: PAM NM_001177306.2 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.844
• Publications: 5 publications found

Genes affected

PAM (HGNC:8596): (peptidylglycine alpha-amidating monooxygenase) This gene encodes a multifunctional protein. The encoded preproprotein is proteolytically processed to generate the mature enzyme. This enzyme includes two domains with distinct catalytic activities, a peptidylglycine alpha-hydroxylating monooxygenase (PHM) domain and a peptidyl-alpha-hydroxyglycine alpha-amidating lyase (PAL) domain. These catalytic domains work sequentially to catalyze the conversion of neuroendocrine peptides to active alpha-amidated products. Alternative splicing results in multiple transcript variants, at least one of which encodes an isoform that is proteolytically processed. [provided by RefSeq, Jan 2016]

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.031).
• BP6: Variant 5-102960019-C-T is Benign according to our data. Variant chr5-102960019-C-T is described in ClinVar as Benign. ClinVar VariationId is 777978.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.844 with no splicing effect.
• BS2: High Homozygotes in GnomAd4 at 8 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001177306.2. 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
	PAM	NM_001177306.2	MANE Select	c.1050C>T	p.Pro350Pro	synonymous	Exon 13 of 26	NP_001170777.1	P19021-1
	PAM	NM_001319943.1		c.1050C>T	p.Pro350Pro	synonymous	Exon 13 of 27	NP_001306872.1	O43832
	PAM	NM_000919.4		c.1050C>T	p.Pro350Pro	synonymous	Exon 13 of 26	NP_000910.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAM	ENST00000438793.8	TSL:1 MANE Select	c.1050C>T	p.Pro350Pro	synonymous	Exon 13 of 26	ENSP00000396493.3	P19021-1
	PAM	ENST00000304400.12	TSL:1	c.1050C>T	p.Pro350Pro	synonymous	Exon 13 of 26	ENSP00000306100.8	A0A8C8KD64
	PAM	ENST00000455264.7	TSL:1	c.1050C>T	p.Pro350Pro	synonymous	Exon 13 of 25	ENSP00000403461.2	P19021-3

Frequencies

GnomAD3 genomes AF: 0.00667 AC: 1013 AN: 151886 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.00210

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00243

Gnomad ASJ AF: 0.00374

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00151

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0124

Gnomad OTH AF: 0.00672

GnomAD2 exomes AF: 0.00700 AC: 1754 AN: 250570 AF XY: 0.00686

Gnomad AFR exome AF: 0.00209

Gnomad AMR exome AF: 0.00319

Gnomad ASJ exome AF: 0.00468

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00282

Gnomad NFE exome AF: 0.0127

Gnomad OTH exome AF: 0.00755

GnomAD4 exome AF: 0.0114 AC: 16577 AN: 1458322 Hom.: 110 Cov.: 29 AF XY: 0.0109 AC XY: 7925 AN XY: 725628

African (AFR) AF: 0.00159 AC: 53 AN: 33384

American (AMR) AF: 0.00311 AC: 139 AN: 44682

Ashkenazi Jewish (ASJ) AF: 0.00452 AC: 118 AN: 26078

East Asian (EAS) AF: 0.00 AC: 0 AN: 39644

South Asian (SAS) AF: 0.000464 AC: 40 AN: 86120

European-Finnish (FIN) AF: 0.00343 AC: 183 AN: 53406

Middle Eastern (MID) AF: 0.00122 AC: 7 AN: 5758

European-Non Finnish (NFE) AF: 0.0140 AC: 15524 AN: 1108994

Other (OTH) AF: 0.00851 AC: 513 AN: 60256

GnomAD4 genome AF: 0.00666 AC: 1013 AN: 152004 Hom.: 8 Cov.: 32 AF XY: 0.00610 AC XY: 453 AN XY: 74296

African (AFR) AF: 0.00210 AC: 87 AN: 41506

American (AMR) AF: 0.00243 AC: 37 AN: 15222

Ashkenazi Jewish (ASJ) AF: 0.00374 AC: 13 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000416 AC: 2 AN: 4810

European-Finnish (FIN) AF: 0.00151 AC: 16 AN: 10572

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0124 AC: 844 AN: 67930

Other (OTH) AF: 0.00665 AC: 14 AN: 2104

Alfa AF: 0.00891 Hom.: 6

Bravo AF: 0.00680

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.0111

EpiControl AF: 0.0121

ClinVar

ClinVar submissions as Germline

Significance: 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	-0.31
CADD	Benign	8.8
DANN	Benign	0.52
PhyloP100		-0.84
Mutation Taster		=292/8	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: rs2217252; hg19: chr5-102295723; COSMIC: COSV57213532;