chr7-246502-G-GGACAGGTGAGCCCTTCCTTCCTCCCTCCATCCGC

Variant names:

• chr7-246502-G-GGACAGGTGAGCCCTTCCTTCCTCCCTCCATCCGC
• rs771282640
• NM_020223.4:c.953_956+30dupACAGGTGAGCCCTTCCTTCCTCCCTCCATCCGCG

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 1P and 16B. PP3 BP6_Very_Strong BA1

The NM_020223.4(FAM20C):​c.953_956+30dupACAGGTGAGCCCTTCCTTCCTCCCTCCATCCGCG variant causes a intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.283 in 1,341,114 control chromosomes in the GnomAD database, including 72,792 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.40 (6675 hom., cov: 40)
  • Exomes 𝑓: 0.27 (66117 hom.)
• Consequence: FAM20C NM_020223.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 8.67
• Publications: 1 publications found

Genes affected

FAM20C (HGNC:22140): (FAM20C golgi associated secretory pathway kinase) This gene encodes a member of the family of secreted protein kinases. The encoded protein binds calcium and phosphorylates proteins involved in bone mineralization. Mutations in this gene are associated with the autosomal recessive disorder Raine syndrome. [provided by RefSeq, Apr 2014]

FAM20C Gene-Disease associations (from GenCC):

• lethal osteosclerotic bone dysplasia

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: G2P, Genomics England PanelApp, Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -15 ACMG points.

• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• BP6: Variant 7-246502-G-GGACAGGTGAGCCCTTCCTTCCTCCCTCCATCCGC is Benign according to our data. Variant chr7-246502-G-GGACAGGTGAGCCCTTCCTTCCTCCCTCCATCCGC is described in ClinVar as Benign. ClinVar VariationId is 402845.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.46 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020223.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FAM20C	NM_020223.4	MANE Select	c.953_956+30dupACAGGTGAGCCCTTCCTTCCTCCCTCCATCCGCG		intron	N/A	NP_064608.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FAM20C	ENST00000313766.6	TSL:1 MANE Select	c.864-11_864-10insGTGAGCCCTTCCTTCCTCCCTCCATCCGCGACAG		intron	N/A	ENSP00000322323.5
	FAM20C	ENST00000515795.1	TSL:1	n.510_511insGTGAGCCCTTCCTTCCTCCCTCCATCCGCGACAG		non_coding_transcript_exon	Exon 1 of 7
	FAM20C	ENST00000942064.1		c.1125-11_1125-10insGTGAGCCCTTCCTTCCTCCCTCCATCCGCGACAG		intron	N/A	ENSP00000612123.1

Frequencies

GnomAD3 genomes AF: 0.397 AC: 43540 AN: 109688 Hom.: 6672 Cov.: 40

Gnomad AFR AF: 0.467

Gnomad AMI AF: 0.491

Gnomad AMR AF: 0.327

Gnomad ASJ AF: 0.379

Gnomad EAS AF: 0.447

Gnomad SAS AF: 0.317

Gnomad FIN AF: 0.349

Gnomad MID AF: 0.489

Gnomad NFE AF: 0.391

Gnomad OTH AF: 0.401

GnomAD4 exome AF: 0.273 AC: 335863 AN: 1231342 Hom.: 66117 Cov.: 34 AF XY: 0.274 AC XY: 167017 AN XY: 610540

African (AFR) AF: 0.244 AC: 6281 AN: 25772

American (AMR) AF: 0.204 AC: 6908 AN: 33926

Ashkenazi Jewish (ASJ) AF: 0.268 AC: 6166 AN: 22966

East Asian (EAS) AF: 0.366 AC: 12536 AN: 34210

South Asian (SAS) AF: 0.236 AC: 17213 AN: 73002

European-Finnish (FIN) AF: 0.270 AC: 9079 AN: 33608

Middle Eastern (MID) AF: 0.308 AC: 1608 AN: 5220

European-Non Finnish (NFE) AF: 0.275 AC: 260963 AN: 950300

Other (OTH) AF: 0.289 AC: 15109 AN: 52338

GnomAD4 genome AF: 0.397 AC: 43564 AN: 109772 Hom.: 6675 Cov.: 40 AF XY: 0.393 AC XY: 21057 AN XY: 53590

African (AFR) AF: 0.468 AC: 10725 AN: 22932

American (AMR) AF: 0.327 AC: 4087 AN: 12512

Ashkenazi Jewish (ASJ) AF: 0.379 AC: 1010 AN: 2666

East Asian (EAS) AF: 0.447 AC: 1927 AN: 4314

South Asian (SAS) AF: 0.317 AC: 1101 AN: 3474

European-Finnish (FIN) AF: 0.349 AC: 2803 AN: 8030

Middle Eastern (MID) AF: 0.483 AC: 117 AN: 242

European-Non Finnish (NFE) AF: 0.391 AC: 20828 AN: 53330

Other (OTH) AF: 0.395 AC: 620 AN: 1568

Alfa AF: 0.204 Hom.: 843

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	2	not specified (2)
-	-	1	FAM20C-related disorder (1)
-	-	1	Lethal osteosclerotic bone dysplasia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.7
Mutation Taster		=14/186	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs771282640; hg19: chr7-286468; COSMIC: COSV58234541;