chr10-4995770-A-C

Variant names:

• chr10-4995770-A-C
• rs13222
• NM_001393392.1:c.666T>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2 PP5 BP4

The NM_001393392.1(AKR1C2):​c.666T>G​(p.His222Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. H222H) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 27)
• Consequence: AKR1C2 NM_001393392.1 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: -4.51
• Publications: 10 publications found

Genes affected

AKR1C2 (HGNC:385): (aldo-keto reductase family 1 member C2) This gene encodes a member of the aldo/keto reductase superfamily, which consists of more than 40 known enzymes and proteins. These enzymes catalyze the conversion of aldehydes and ketones to their corresponding alcohols using NADH and/or NADPH as cofactors. The enzymes display overlapping but distinct substrate specificity. This enzyme binds bile acid with high affinity, and shows minimal 3-alpha-hydroxysteroid dehydrogenase activity. This gene shares high sequence identity with three other gene members and is clustered with those three genes at chromosome 10p15-p14. Three transcript variants encoding two different isoforms have been found for this gene. [provided by RefSeq, Dec 2011]

AKR1C2 Gene-Disease associations (from GenCC):

• 46,XY disorder of sex development due to testicular 17,20-desmolase deficiency

  Inheritance: AR Classification: SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet

ENSG00000224251 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 10-4995770-A-C is Pathogenic according to our data. Variant chr10-4995770-A-C is described in ClinVar as Pathogenic. ClinVar VariationId is 30067.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.03474471). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AKR1C2	NM_001393392.1	c.666T>G	p.His222Gln	missense_variant	Exon 6 of 9	ENST00000380753.9	NP_001380321.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AKR1C2	ENST00000380753.9	c.666T>G	p.His222Gln	missense_variant	Exon 6 of 9	1	NM_001393392.1	ENSP00000370129.4

Frequencies

GnomAD3 genomes Cov.: 27

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 27

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

46,XY disorder of sex development due to testicular 17,20-desmolase deficiency Pathogenic:1

Aug 12, 2011

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	0.0010
DANN	Benign	0.50
DEOGEN2	Benign	0.024	T;.
Eigen	Benign	-2.2
Eigen_PC	Benign	-2.2
FATHMM_MKL	Benign	0.0078	N
LIST_S2	Benign	0.59	T;T
M_CAP	Benign	0.0011	T
MetaRNN	Benign	0.035	T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-0.60	N;.
PhyloP100		-4.5
PrimateAI	Benign	0.40	T
PROVEAN	Benign	1.7	N;N
REVEL	Uncertain	0.34
Sift	Benign	1.0	T;T
Sift4G	Benign	0.58	T;T
Polyphen		0.0	B;B
Vest4		0.17
MutPred		0.65		Loss of glycosylation at S217 (P = 0.1616);.;
MVP		0.10
MPC		1.7
ClinPred		0.083	T
GERP RS		-5.0
Varity_R		0.63
gMVP		0.45
Mutation Taster		=5/95	disease causing (ClinVar)

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: rs13222; hg19: chr10-5037962;