2-101412995-C-T

Variant names:

• chr2-101412995-C-T
• rs1365210148
• NM_001145664.2:c.638G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001145664.2(RFX8):​c.638G>A​(p.Gly213Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000714 in 1,399,704 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. 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. G213A) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: RFX8 NM_001145664.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.143
• Publications: 0 publications found

Genes affected

RFX8 (HGNC:37253): (regulatory factor X8) Predicted to enable DNA-binding transcription factor activity, RNA polymerase II-specific and RNA polymerase II cis-regulatory region sequence-specific DNA binding activity. Predicted to be involved in regulation of transcription by RNA polymerase II. Predicted to be located in nucleus. Predicted to be part of chromatin. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.051126808).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001145664.2. 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
	RFX8	NM_001145664.2	MANE Select	c.638G>A	p.Gly213Asp	missense	Exon 8 of 12	NP_001139136.2	Q6ZV50-3
	RFX8	NM_001367508.1		c.125G>A	p.Gly42Asp	missense	Exon 9 of 13	NP_001354437.1
	RFX8	NM_001367509.1		c.125G>A	p.Gly42Asp	missense	Exon 10 of 14	NP_001354438.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RFX8	ENST00000428343.6	TSL:2 MANE Select	c.638G>A	p.Gly213Asp	missense	Exon 8 of 12	ENSP00000401536.1	Q6ZV50-3
	RFX8	ENST00000646893.2		c.977G>A	p.Gly326Asp	missense	Exon 11 of 15	ENSP00000494249.2	Q6ZV50-1
	RFX8	ENST00000646446.1		c.851G>A	p.Gly284Asp	missense	Exon 11 of 15	ENSP00000494216.1	A0A2R8Y560

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.14e-7 AC: 1 AN: 1399704 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 690356

African (AFR) AF: 0.00 AC: 0 AN: 31598

American (AMR) AF: 0.00 AC: 0 AN: 35696

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25180

East Asian (EAS) AF: 0.00 AC: 0 AN: 35738

South Asian (SAS) AF: 0.00 AC: 0 AN: 79236

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49456

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5702

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1078998

Other (OTH) AF: 0.0000172 AC: 1 AN: 58100

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	10
DANN	Benign	0.83
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.026	N
LIST_S2	Benign	0.33	T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.051	T
MetaSVM	Benign	-0.93	T
PhyloP100		0.14
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.46	N
REVEL	Benign	0.10
Sift	Benign	0.20	T
Sift4G	Pathogenic	0.0	D
Polyphen		0.039	B
Vest4		0.18
MVP		0.014
MPC		0.00040
ClinPred		0.061	T
GERP RS		1.5
gMVP		0.24
Mutation Taster		=91/9	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: rs1365210148; hg19: chr2-102029457;