2-170716869-G-A

Variant names:

• chr2-170716869-G-A
• rs1427621549
• NM_001003845.3:c.662G>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001003845.3(SP5):​c.662G>A​(p.Arg221His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000204 in 1,470,546 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 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. R221P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000022 (0 hom.)
• Consequence: SP5 NM_001003845.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.41
• Publications: 0 publications found

Genes affected

SP5 (HGNC:14529): (Sp5 transcription factor) 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 act upstream of or within bone morphogenesis; cellular response to organic cyclic compound; and post-anal tail morphogenesis. Predicted to be located in nucleus. Predicted to be part of chromatin. [provided by Alliance of Genome Resources, Apr 2022]

ERICH2-DT (HGNC:55686): (ERICH2 divergent transcript)

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.19384006).
• BS2: High AC in GnomAdExome4 at 29 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001003845.3. 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
	SP5	NM_001003845.3	MANE Select	c.662G>A	p.Arg221His	missense	Exon 2 of 2	NP_001003845.1	Q6BEB4
	ERICH2-DT	NR_110185.1		n.376+6635C>T		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SP5	ENST00000375281.4	TSL:1 MANE Select	c.662G>A	p.Arg221His	missense	Exon 2 of 2	ENSP00000364430.3	Q6BEB4
	ERICH2-DT	ENST00000662274.1		n.859+6635C>T		intron	N/A
	ERICH2-DT	ENST00000671292.2		n.387+6635C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 151898 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00 AC: 0 AN: 77988 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000220 AC: 29 AN: 1318648 Hom.: 0 Cov.: 33 AF XY: 0.0000277 AC XY: 18 AN XY: 649846

African (AFR) AF: 0.0000390 AC: 1 AN: 25640

American (AMR) AF: 0.00 AC: 0 AN: 21020

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22202

East Asian (EAS) AF: 0.00 AC: 0 AN: 29392

South Asian (SAS) AF: 0.00 AC: 0 AN: 69362

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46590

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3834

European-Non Finnish (NFE) AF: 0.0000268 AC: 28 AN: 1046528

Other (OTH) AF: 0.00 AC: 0 AN: 54080

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 151898 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74194

African (AFR) AF: 0.00 AC: 0 AN: 41398

American (AMR) AF: 0.00 AC: 0 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5162

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10544

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67924

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.70
Eigen_PC	Benign	-0.68
FATHMM_MKL	Benign	0.71	D
LIST_S2	Benign	0.67	T
M_CAP	Pathogenic	0.64	D
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	0.0	N
PhyloP100		1.4
PrimateAI	Pathogenic	0.92	D
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.16
Sift	Benign	0.070	T
Sift4G	Benign	0.59	T
Polyphen		0.91	P
Vest4		0.13
MutPred		0.18		Loss of methylation at R221 (P = 0.0268)
MVP		0.088
ClinPred		0.54	D
GERP RS		3.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.18
gMVP		0.43
Mutation Taster		=78/22	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: rs1427621549; hg19: chr2-171573379;