rs2302235

Variant names:

• chr17-68542277-G-A
• rs2302235
• NM_017565.4:c.929-112C>T

Your query was ambiguous. Multiple possible variants found:

• chr17-68542277-G-A
• chr17-68542277-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_017565.4(FAM20A):​c.929-112C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.137 in 1,154,794 control chromosomes in the GnomAD database, including 11,457 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1396 hom., cov: 32)
  • Exomes 𝑓: 0.14 (10061 hom.)
• Consequence: FAM20A NM_017565.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.493
• Publications: 8 publications found

Genes affected

FAM20A (HGNC:23015): (FAM20A golgi associated secretory pathway pseudokinase) This locus encodes a protein that is likely secreted and may function in hematopoiesis. A mutation at this locus has been associated with amelogenesis imperfecta and gingival hyperplasia syndrome. Alternatively spliced transcript variants have been identified. [provided by RefSeq, Aug 2011]

PRKAR1A (HGNC:9388): (protein kinase cAMP-dependent type I regulatory subunit alpha) cAMP is a signaling molecule important for a variety of cellular functions. cAMP exerts its effects by activating the cAMP-dependent protein kinase, which transduces the signal through phosphorylation of different target proteins. The inactive kinase holoenzyme is a tetramer composed of two regulatory and two catalytic subunits. cAMP causes the dissociation of the inactive holoenzyme into a dimer of regulatory subunits bound to four cAMP and two free monomeric catalytic subunits. Four different regulatory subunits and three catalytic subunits have been identified in humans. This gene encodes one of the regulatory subunits. This protein was found to be a tissue-specific extinguisher that down-regulates the expression of seven liver genes in hepatoma x fibroblast hybrids. Mutations in this gene cause Carney complex (CNC). This gene can fuse to the RET protooncogene by gene rearrangement and form the thyroid tumor-specific chimeric oncogene known as PTC2. A nonconventional nuclear localization sequence (NLS) has been found for this protein which suggests a role in DNA replication via the protein serving as a nuclear transport protein for the second subunit of the Replication Factor C (RFC40). Several alternatively spliced transcript variants encoding two different isoforms have been observed. [provided by RefSeq, Jan 2013]

PRKAR1A Gene-Disease associations (from GenCC):

• Acrodysostosis 1 with or without hormone resistance

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• acrodysostosis with multiple hormone resistance

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, Illumina
• Carney complex, type 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae), G2P
• pigmented nodular adrenocortical disease, primary, 1

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Genomics England PanelApp, Ambry Genetics
• acrodysostosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Carney complex

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial atrial myxoma

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• primary pigmented nodular adrenocortical disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 17-68542277-G-A is Benign according to our data. Variant chr17-68542277-G-A is described in ClinVar as Benign. ClinVar VariationId is 1237093.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.188 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017565.4. 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
	FAM20A	NM_017565.4	MANE Select	c.929-112C>T		intron	N/A	NP_060035.2	Q96MK3
	FAM20A	NM_001243746.2		c.515-112C>T		intron	N/A	NP_001230675.1
	PRKAR1A	NM_001276290.1		c.974-8807G>A		intron	N/A	NP_001263219.1	P10644-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FAM20A	ENST00000592554.2	TSL:1 MANE Select	c.929-112C>T		intron	N/A	ENSP00000468308.1	Q96MK3
	FAM20A	ENST00000226094.9	TSL:1	n.582-112C>T		intron	N/A
	FAM20A	ENST00000882126.1		c.929-112C>T		intron	N/A	ENSP00000552185.1

Frequencies

GnomAD3 genomes AF: 0.134 AC: 20316 AN: 152022 Hom.: 1396 Cov.: 32

Gnomad AFR AF: 0.123

Gnomad AMI AF: 0.151

Gnomad AMR AF: 0.154

Gnomad ASJ AF: 0.120

Gnomad EAS AF: 0.170

Gnomad SAS AF: 0.199

Gnomad FIN AF: 0.105

Gnomad MID AF: 0.0791

Gnomad NFE AF: 0.133

Gnomad OTH AF: 0.132

GnomAD4 exome AF: 0.138 AC: 138355 AN: 1002654 Hom.: 10061 AF XY: 0.140 AC XY: 71572 AN XY: 509906

African (AFR) AF: 0.123 AC: 2928 AN: 23844

American (AMR) AF: 0.170 AC: 5826 AN: 34346

Ashkenazi Jewish (ASJ) AF: 0.117 AC: 2547 AN: 21708

East Asian (EAS) AF: 0.166 AC: 5707 AN: 34406

South Asian (SAS) AF: 0.191 AC: 13447 AN: 70354

European-Finnish (FIN) AF: 0.107 AC: 4701 AN: 43884

Middle Eastern (MID) AF: 0.101 AC: 496 AN: 4900

European-Non Finnish (NFE) AF: 0.133 AC: 96552 AN: 724404

Other (OTH) AF: 0.137 AC: 6151 AN: 44808

GnomAD4 genome AF: 0.134 AC: 20320 AN: 152140 Hom.: 1396 Cov.: 32 AF XY: 0.134 AC XY: 9950 AN XY: 74386

African (AFR) AF: 0.123 AC: 5103 AN: 41488

American (AMR) AF: 0.154 AC: 2355 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.120 AC: 417 AN: 3472

East Asian (EAS) AF: 0.170 AC: 879 AN: 5176

South Asian (SAS) AF: 0.198 AC: 954 AN: 4814

European-Finnish (FIN) AF: 0.105 AC: 1114 AN: 10598

Middle Eastern (MID) AF: 0.0816 AC: 24 AN: 294

European-Non Finnish (NFE) AF: 0.133 AC: 9061 AN: 67992

Other (OTH) AF: 0.130 AC: 276 AN: 2116

Alfa AF: 0.137 Hom.: 304

Bravo AF: 0.139

Asia WGS AF: 0.187 AC: 649 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	8.4
DANN	Benign	0.60
PhyloP100		0.49
Mutation Taster		=100/0	polymorphism (auto)

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: rs2302235; hg19: chr17-66538418; COSMIC: COSV56836065; COSMIC: COSV56836065;