6-50823871-C-CACAA

Position:

• chr6-50823871-C-CACAA

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The ENST00000393655.4(TFAP2B):​c.540+6_540+7insACAA variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0025 (0 hom., cov: 0)
  • Exomes 𝑓: 0.0011 (11 hom.)
• Consequence: TFAP2B ENST00000393655.4 splice_region, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:3
• Conservation: PhyloP100: 0.0710

Genes affected

TFAP2B (HGNC:11743): (transcription factor AP-2 beta) This gene encodes a member of the AP-2 family of transcription factors. AP-2 proteins form homo- or hetero-dimers with other AP-2 family members and bind specific DNA sequences. They are thought to stimulate cell proliferation and suppress terminal differentiation of specific cell types during embryonic development. Specific AP-2 family members differ in their expression patterns and binding affinity for different promoters. This protein functions as both a transcriptional activator and repressor. Mutations in this gene result in autosomal dominant Char syndrome, suggesting that this gene functions in the differentiation of neural crest cell derivatives. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP6: Variant 6-50823871-C-CACAA is Benign according to our data. Variant chr6-50823871-C-CACAA is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 357277.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Benign=1}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00252 (382/151390) while in subpopulation AFR AF= 0.00525 (216/41122). AF 95% confidence interval is 0.00468. There are 0 homozygotes in gnomad4. There are 184 alleles in male gnomad4 subpopulation. Median coverage is 0. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 382 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TFAP2B	NM_003221.4	c.540+28_540+31dupCAAA		intron_variant		ENST00000393655.4	NP_003212.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TFAP2B	ENST00000393655.4	c.540+6_540+7insACAA		splice_region_variant, intron_variant		1	NM_003221.4	ENSP00000377265.2
TFAP2B	ENST00000344788.7	c.534+6_534+7insACAA		splice_region_variant, intron_variant		3		ENSP00000342252.3
TFAP2B	ENST00000489228.1	n.*6_*7insACAA		downstream_gene_variant		2

Frequencies

GnomAD3 genomes AF: 0.00250 AC: 378 AN: 151274 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00517

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000920

Gnomad ASJ AF: 0.0309

Gnomad EAS AF: 0.000390

Gnomad SAS AF: 0.000417

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00321

Gnomad NFE AF: 0.000515

Gnomad OTH AF: 0.00240

GnomAD3 exomes AF: 0.00289 AC: 392 AN: 135480 Hom.: 3 AF XY: 0.00274 AC XY: 202 AN XY: 73818

Gnomad AFR exome AF: 0.00488

Gnomad AMR exome AF: 0.000892

Gnomad ASJ exome AF: 0.0338

Gnomad EAS exome AF: 0.000555

Gnomad SAS exome AF: 0.000177

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000749

Gnomad OTH exome AF: 0.00341

GnomAD4 exome AF: 0.00114 AC: 1588 AN: 1387008 Hom.: 11 Cov.: 0 AF XY: 0.00116 AC XY: 796 AN XY: 684848

Gnomad4 AFR exome AF: 0.00572

Gnomad4 AMR exome AF: 0.000891

Gnomad4 ASJ exome AF: 0.0321

Gnomad4 EAS exome AF: 0.000112

Gnomad4 SAS exome AF: 0.000290

Gnomad4 FIN exome AF: 0.0000261

Gnomad4 NFE exome AF: 0.000353

Gnomad4 OTH exome AF: 0.00269

GnomAD4 genome AF: 0.00252 AC: 382 AN: 151390 Hom.: 0 Cov.: 0 AF XY: 0.00249 AC XY: 184 AN XY: 73918

Gnomad4 AFR AF: 0.00525

Gnomad4 AMR AF: 0.000919

Gnomad4 ASJ AF: 0.0309

Gnomad4 EAS AF: 0.000391

Gnomad4 SAS AF: 0.000417

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000515

Gnomad4 OTH AF: 0.00238

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 09, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Char syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs368226832; hg19: chr6-50791584;