2-170717087-A-C

Position:

• chr2-170717087-A-C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001003845.3(SP5):​c.880A>C​(p.Lys294Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000379 in 1,570,568 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00039 (1 hom.)
• Consequence: SP5 NM_001003845.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.02

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

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.016926944).
• BS2: High AC in GnomAd4 at 40 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SP5	NM_001003845.3	c.880A>C	p.Lys294Gln	missense_variant	2/2	ENST00000375281.4	NP_001003845.1
ERICH2-DT	NR_110185.1	n.376+6417T>G		intron_variant, non_coding_transcript_variant
SP5	XM_005246542.5	c.1012A>C	p.Lys338Gln	missense_variant	2/2		XP_005246599.1
SP5	XM_047444264.1	c.652A>C	p.Lys218Gln	missense_variant	2/2		XP_047300220.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SP5	ENST00000375281.4	c.880A>C	p.Lys294Gln	missense_variant	2/2	1	NM_001003845.3	ENSP00000364430	P1
ERICH2-DT	ENST00000662274.1	n.859+6417T>G		intron_variant, non_coding_transcript_variant
ERICH2-DT	ENST00000671292.1	n.336+6417T>G		intron_variant, non_coding_transcript_variant
ERICH2-DT	ENST00000690230.1	n.404+6417T>G		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.000263 AC: 40 AN: 152206 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000367

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000279 AC: 50 AN: 179390 Hom.: 0 AF XY: 0.000368 AC XY: 36 AN XY: 97904

Gnomad AFR exome AF: 0.000307

Gnomad AMR exome AF: 0.000146

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000711

Gnomad FIN exome AF: 0.000123

Gnomad NFE exome AF: 0.000298

Gnomad OTH exome AF: 0.000207

GnomAD4 exome AF: 0.000391 AC: 555 AN: 1418244 Hom.: 1 Cov.: 33 AF XY: 0.000399 AC XY: 280 AN XY: 702274

Gnomad4 AFR exome AF: 0.000277

Gnomad4 AMR exome AF: 0.000182

Gnomad4 ASJ exome AF: 0.0000393

Gnomad4 EAS exome AF: 0.000107

Gnomad4 SAS exome AF: 0.000575

Gnomad4 FIN exome AF: 0.000143

Gnomad4 NFE exome AF: 0.000426

Gnomad4 OTH exome AF: 0.000256

GnomAD4 genome AF: 0.000263 AC: 40 AN: 152324 Hom.: 0 Cov.: 33 AF XY: 0.000282 AC XY: 21 AN XY: 74476

Gnomad4 AFR AF: 0.000216

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.000368

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000248 Hom.: 0

Bravo AF: 0.000253

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000589 AC: 5

ExAC AF: 0.000270 AC: 32

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 27, 2022

The c.880A>C (p.K294Q) alteration is located in exon 2 (coding exon 2) of the SP5 gene. This alteration results from a A to C substitution at nucleotide position 880, causing the lysine (K) at amino acid position 294 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.71
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.41
CADD	Pathogenic	33
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.46	T
Eigen	Benign	0.070
Eigen_PC	Benign	0.094
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.017	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.9	M
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-3.5	D
REVEL	Benign	0.18
Sift	Uncertain	0.012	D
Sift4G	Uncertain	0.047	D
Polyphen		0.68	P
Vest4		0.35
MVP		0.088
ClinPred		0.085	T
GERP RS		3.7
Varity_R		0.52
gMVP		0.60

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

Publications

LitVar

Other links and lift over

dbSNP: rs200305999; hg19: chr2-171573597; COSMIC: COSV100935234; COSMIC: COSV100935234;