14-21523010-C-G

Position:

• chr14-21523010-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001364564.1(SALL2):​c.2712G>C​(p.Glu904Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00981 in 1,614,116 control chromosomes in the GnomAD database, including 1,245 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar.

• Frequency:
  • Genomes: 𝑓 0.051 (623 hom., cov: 32)
  • Exomes 𝑓: 0.0055 (622 hom.)
• Consequence: SALL2 NM_001364564.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.247

Genes affected

SALL2 (HGNC:10526): (spalt like transcription factor 2) This gene encodes a protein containing multiple zinc finger domains. The encoded protein functions in optical fissure closure during development of the eye in the embryo. Mutations in this gene are associated with ocular coloboma. [provided by RefSeq, Jul 2016]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0015507042).
• BP6: Variant 14-21523010-C-G is Benign according to our data. Variant chr14-21523010-C-G is described in ClinVar as [Benign]. Clinvar id is 2040752.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.173 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SALL2	NM_001364564.1	c.2712G>C	p.Glu904Asp	missense_variant	2/2	ENST00000537235.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SALL2	ENST00000537235.2	c.2712G>C	p.Glu904Asp	missense_variant	2/2	2	NM_001364564.1	P3

Frequencies

GnomAD3 genomes AF: 0.0509 AC: 7748 AN: 152138 Hom.: 615 Cov.: 32

Gnomad AFR AF: 0.176

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0200

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000809

Gnomad OTH AF: 0.0351

GnomAD3 exomes AF: 0.0137 AC: 3447 AN: 251452 Hom.: 265 AF XY: 0.00995 AC XY: 1352 AN XY: 135894

Gnomad AFR exome AF: 0.181

Gnomad AMR exome AF: 0.00888

Gnomad ASJ exome AF: 0.00377

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.000621

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000730

Gnomad OTH exome AF: 0.00847

GnomAD4 exome AF: 0.00550 AC: 8044 AN: 1461860 Hom.: 622 Cov.: 34 AF XY: 0.00482 AC XY: 3505 AN XY: 727230

Gnomad4 AFR exome AF: 0.184

Gnomad4 AMR exome AF: 0.0103

Gnomad4 ASJ exome AF: 0.00451

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000638

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000343

Gnomad4 OTH exome AF: 0.0132

GnomAD4 genome AF: 0.0512 AC: 7789 AN: 152256 Hom.: 623 Cov.: 32 AF XY: 0.0497 AC XY: 3702 AN XY: 74460

Gnomad4 AFR AF: 0.177

Gnomad4 AMR AF: 0.0199

Gnomad4 ASJ AF: 0.00259

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000809

Gnomad4 OTH AF: 0.0347

Alfa AF: 0.00626 Hom.: 12

Bravo AF: 0.0580

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.166 AC: 732

ESP6500EA AF: 0.000930 AC: 8

ExAC AF: 0.0169 AC: 2046

Asia WGS AF: 0.0110 AC: 37 AN: 3478

EpiCase AF: 0.000818

EpiControl AF: 0.000593

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 25, 2024

- -

SALL2-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 23, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.79	T
BayesDel_noAF	Benign	-0.77
CADD	Benign	4.5
DANN	Benign	0.91
Eigen	Benign	-0.88
Eigen_PC	Benign	-0.94
FATHMM_MKL	Benign	0.44	N
MetaRNN	Benign	0.0016	T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	P;P;P;P
PrimateAI	Benign	0.41	T
Sift4G	Benign	0.35	T;T
Polyphen		0.0	.;B
Vest4		0.028
MutPred		0.25		Loss of glycosylation at P904 (P = 0.102);.;
ClinPred		0.0045	T
GERP RS		-0.41
gMVP		0.13

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: rs61736009; hg19: chr14-21991144;