6-50823524-C-G

Variant names:

• chr6-50823524-C-G
• rs2113929335
• NM_003221.4:c.199C>G

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 3P and 4B. PM2 PP2 BS2

The NM_003221.4(TFAP2B):​c.199C>G​(p.Pro67Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00000342 in 1,461,718 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P67S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: TFAP2B NM_003221.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.07
• Publications: 0 publications found

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]

TFAP2B Gene-Disease associations (from GenCC):

• Char syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, PanelApp Australia, G2P
• TFAP2B-related congenital heart disease spectrum disorder

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• patent ductus arteriosus 2

  Inheritance: AD Classification: STRONG Submitted by: PanelApp Australia
• familial patent arterial duct

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 8 curated pathogenic missense variants (we use a threshold of 10). The gene has 2 curated benign missense variants. Gene score misZ: 1.2875 (below the threshold of 3.09). Trascript score misZ: 1.6268 (below the threshold of 3.09). GenCC associations: The gene is linked to familial patent arterial duct, Char syndrome.
• BS2: High AC in GnomAdExome4 at 5 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003221.4. 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
	TFAP2B	NM_003221.4	MANE Select	c.199C>G	p.Pro67Ala	missense	Exon 2 of 7	NP_003212.2	Q92481-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TFAP2B	ENST00000393655.4	TSL:1 MANE Select	c.199C>G	p.Pro67Ala	missense	Exon 2 of 7	ENSP00000377265.2	Q92481-1
	TFAP2B	ENST00000344788.7	TSL:3	c.193C>G	p.Pro65Ala	missense	Exon 3 of 4	ENSP00000342252.3	X6R4Y8
	TFAP2B	ENST00000489228.1	TSL:2	n.494C>G		non_coding_transcript_exon	Exon 2 of 2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461718 Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 2 AN XY: 727150

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.00 AC: 0 AN: 86224

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53404

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1111938

Other (OTH) AF: 0.00 AC: 0 AN: 60386

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.79
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.070
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.86	D
Eigen	Benign	0.14
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.099	D
MetaRNN	Uncertain	0.72	D
MetaSVM	Uncertain	0.17	D
MutationAssessor	Uncertain	2.8	M
PhyloP100		6.1
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-6.2	D
REVEL	Uncertain	0.63
Sift	Benign	0.10	T
Sift4G	Pathogenic	0.0	D
Polyphen		0.088	B
Vest4		0.68
MutPred		0.54		Loss of catalytic residue at P67 (P = 0.0615)
MVP		0.74
MPC		1.6
ClinPred		0.99	D
GERP RS		4.4
Varity_R		0.32
gMVP		0.61
Mutation Taster		=57/43	polymorphism

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: rs2113929335; hg19: chr6-50791237;