rs2361636

Variant names:

• chrX-67645742-G-A
• rs2361636
• NM_000044.6:c.1768+2335G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000044.6(AR):​c.1768+2335G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0574 in 109,462 control chromosomes in the GnomAD database, including 473 homozygotes. There are 1,557 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.057 (473 hom., 1557 hem., cov: 22)
• Consequence: AR NM_000044.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.551
• Publications: 1 publications found

Genes affected

AR (HGNC:644): (androgen receptor) The androgen receptor gene is more than 90 kb long and codes for a protein that has 3 major functional domains: the N-terminal domain, DNA-binding domain, and androgen-binding domain. The protein functions as a steroid-hormone activated transcription factor. Upon binding the hormone ligand, the receptor dissociates from accessory proteins, translocates into the nucleus, dimerizes, and then stimulates transcription of androgen responsive genes. This gene contains 2 polymorphic trinucleotide repeat segments that encode polyglutamine and polyglycine tracts in the N-terminal transactivation domain of its protein. Expansion of the polyglutamine tract from the normal 9-34 repeats to the pathogenic 38-62 repeats causes spinal bulbar muscular atrophy (SBMA, also known as Kennedy's disease). Mutations in this gene are also associated with complete androgen insensitivity (CAIS). Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jan 2017]

AR Gene-Disease associations (from GenCC):

• androgen insensitivity syndrome

  Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Laboratory for Molecular Medicine, G2P, Labcorp Genetics (formerly Invitae)
• Kennedy disease

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, ClinGen, G2P, Labcorp Genetics (formerly Invitae), Orphanet
• partial androgen insensitivity syndrome

  Inheritance: XL Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet
• complete androgen insensitivity syndrome

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.01).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.194 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000044.6. 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
	AR	NM_000044.6	MANE Select	c.1768+2335G>A		intron	N/A	NP_000035.2
	AR	NM_001348063.1		c.1768+2335G>A		intron	N/A	NP_001334992.1	Q9NUA2
	AR	NM_001348061.1		c.1768+2335G>A		intron	N/A	NP_001334990.1	Q9NUA2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AR	ENST00000374690.9	TSL:1 MANE Select	c.1768+2335G>A		intron	N/A	ENSP00000363822.3	P10275-1
	AR	ENST00000396044.8	TSL:1	c.1768+2335G>A		intron	N/A	ENSP00000379359.3	F5GZG9
	AR	ENST00000504326.5	TSL:1	c.1768+2335G>A		intron	N/A	ENSP00000421155.1	P10275-3

Frequencies

GnomAD3 genomes AF: 0.0574 AC: 6275 AN: 109411 Hom.: 473 Cov.: 22

Gnomad AFR AF: 0.198

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0211

Gnomad ASJ AF: 0.000381

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00353

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0302

Gnomad NFE AF: 0.000741

Gnomad OTH AF: 0.0500

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0574 AC: 6284 AN: 109462 Hom.: 473 Cov.: 22 AF XY: 0.0488 AC XY: 1557 AN XY: 31930

African (AFR) AF: 0.198 AC: 5941 AN: 29942

American (AMR) AF: 0.0211 AC: 216 AN: 10225

Ashkenazi Jewish (ASJ) AF: 0.000381 AC: 1 AN: 2624

East Asian (EAS) AF: 0.00 AC: 0 AN: 3439

South Asian (SAS) AF: 0.00314 AC: 8 AN: 2544

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5715

Middle Eastern (MID) AF: 0.0332 AC: 7 AN: 211

European-Non Finnish (NFE) AF: 0.000722 AC: 38 AN: 52603

Other (OTH) AF: 0.0493 AC: 73 AN: 1480

Alfa AF: 0.0497 Hom.: 584

Bravo AF: 0.0664

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	1.3
DANN	Benign	0.67
PhyloP100		0.55
Mutation Taster		=100/0	polymorphism (auto)

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: rs2361636; hg19: chrX-66865584;