3-181712330-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Moderate BP6_Moderate BS1 BS2

The NM_003106.4(SOX2):c.-31C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00468 in 1,341,842 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0045 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0047 (21 hom.)
• Consequence: SOX2 NM_003106.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.417

Genes affected

SOX2 (HGNC:11195): (SRY-box transcription factor 2) This intronless gene encodes a member of the SRY-related HMG-box (SOX) family of transcription factors involved in the regulation of embryonic development and in the determination of cell fate. The product of this gene is required for stem-cell maintenance in the central nervous system, and also regulates gene expression in the stomach. Mutations in this gene have been associated with optic nerve hypoplasia and with syndromic microphthalmia, a severe form of structural eye malformation. This gene lies within an intron of another gene called SOX2 overlapping transcript (SOX2OT). [provided by RefSeq, Jul 2008]

SOX2-OT (HGNC:20209): (SOX2 overlapping transcript) This gene produces alternatively spliced long non-coding RNAs. These RNAs were observed to be upregulated in tumor cells and positively correlated to expression of the SRY-box 2 gene. Overexpression of these transcripts may promote cell proliferation. [provided by RefSeq, Dec 2017]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.29).
• BP6: Variant 3-181712330-C-T is Benign according to our data. Variant chr3-181712330-C-T is described in ClinVar as [Benign]. Clinvar id is 378636.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00454 (689/151672) while in subpopulation NFE AF= 0.00535 (363/67790). AF 95% confidence interval is 0.0049. There are 2 homozygotes in gnomad4. There are 300 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 680 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SOX2	NM_003106.4	c.-31C>T		5_prime_UTR_variant	1/1	ENST00000325404.3
SOX2-OT	NR_075091.1	n.783-2855C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SOX2	ENST00000325404.3	c.-31C>T		5_prime_UTR_variant	1/1		NM_003106.4	P1
SOX2-OT	ENST00000626948.3	n.837-2855C>T		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.00449 AC: 680 AN: 151562 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00385

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00407

Gnomad ASJ AF: 0.0161

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.00152

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00537

Gnomad OTH AF: 0.00527

GnomAD3 exomes AF: 0.00363 AC: 30 AN: 8268 Hom.: 0 AF XY: 0.00361 AC XY: 16 AN XY: 4432

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00704

Gnomad ASJ exome AF: 0.0250

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00769

Gnomad FIN exome AF: 0.00162

Gnomad NFE exome AF: 0.00678

Gnomad OTH exome AF: 0.00758

GnomAD4 exome AF: 0.00470 AC: 5592 AN: 1190170 Hom.: 21 Cov.: 32 AF XY: 0.00467 AC XY: 2677 AN XY: 573066

Gnomad4 AFR exome AF: 0.00361

Gnomad4 AMR exome AF: 0.00393

Gnomad4 ASJ exome AF: 0.0147

Gnomad4 EAS exome AF: 0.0000361

Gnomad4 SAS exome AF: 0.00123

Gnomad4 FIN exome AF: 0.00204

Gnomad4 NFE exome AF: 0.00492

Gnomad4 OTH exome AF: 0.00515

GnomAD4 genome AF: 0.00454 AC: 689 AN: 151672 Hom.: 2 Cov.: 32 AF XY: 0.00405 AC XY: 300 AN XY: 74128

Gnomad4 AFR AF: 0.00408

Gnomad4 AMR AF: 0.00406

Gnomad4 ASJ AF: 0.0161

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.00152

Gnomad4 NFE AF: 0.00535

Gnomad4 OTH AF: 0.00522

Alfa AF: 0.00434 Hom.: 0

Bravo AF: 0.00437

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 26, 2015

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.29
Cadd	Benign	17
Dann	Uncertain	0.98

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: rs56073304; hg19: chr3-181430118;