rs746592679

Variant names:

• chr19-10581380-C-A
• rs746592679
• NM_005498.5:c.559G>T

Your query was ambiguous. Multiple possible variants found:

• chr19-10581380-C-A
• chr19-10581380-C-T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_005498.5(AP1M2):​c.559G>T​(p.Gly187Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,138 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G187S) has been classified as Uncertain significance.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: AP1M2 NM_005498.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.89
• Publications: 0 publications found

Genes affected

AP1M2 (HGNC:558): (adaptor related protein complex 1 subunit mu 2) This gene encodes a subunit of the heterotetrameric adaptor-related protein comlex 1 (AP-1), which belongs to the adaptor complexes medium subunits family. This protein is capable of interacting with tyrosine-based sorting signals. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2014]

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.983

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005498.5. 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
	AP1M2	NM_005498.5	MANE Select	c.559G>T	p.Gly187Cys	missense	Exon 6 of 12	NP_005489.2
	AP1M2	NM_001300887.2		c.559G>T	p.Gly187Cys	missense	Exon 6 of 12	NP_001287816.1	Q9Y6Q5-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AP1M2	ENST00000250244.11	TSL:1 MANE Select	c.559G>T	p.Gly187Cys	missense	Exon 6 of 12	ENSP00000250244.5	Q9Y6Q5-1
	AP1M2	ENST00000590923.5	TSL:1	c.559G>T	p.Gly187Cys	missense	Exon 6 of 12	ENSP00000465685.1	Q9Y6Q5-2
	AP1M2	ENST00000918520.1		c.559G>T	p.Gly187Cys	missense	Exon 6 of 12	ENSP00000588579.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152138 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 33

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152138 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74328

African (AFR) AF: 0.00 AC: 0 AN: 41416

American (AMR) AF: 0.00 AC: 0 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Benign	0.35	T
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Benign	0.75	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Benign	0.059	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	0.21	D
MutationAssessor	Pathogenic	4.3	H
PhyloP100		7.9
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-8.1	D
REVEL	Pathogenic	0.66
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.95
MutPred		0.94		Gain of sheet (P = 0.1208)
MVP		0.71
MPC		0.68
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.90
gMVP		0.74
Mutation Taster		=20/80	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs746592679; hg19: chr19-10692056;