22-50695096-C-T

Position:

• chr22-50695096-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_001372044.2(SHANK3):​c.1527+50C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0163 in 1,416,160 control chromosomes in the GnomAD database, including 363 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.025 (56 hom., cov: 33)
  • Exomes 𝑓: 0.015 (307 hom.)
• Consequence: SHANK3 NM_001372044.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -4.51

Genes affected

SHANK3 (HGNC:14294): (SH3 and multiple ankyrin repeat domains 3) This gene is a member of the Shank gene family. Shank proteins are multidomain scaffold proteins of the postsynaptic density that connect neurotransmitter receptors, ion channels, and other membrane proteins to the actin cytoskeleton and G-protein-coupled signaling pathways. Shank proteins also play a role in synapse formation and dendritic spine maturation. Mutations in this gene are a cause of autism spectrum disorder (ASD), which is characterized by impairments in social interaction and communication, and restricted behavioral patterns and interests. Mutations in this gene also cause schizophrenia type 15, and are a major causative factor in the neurological symptoms of 22q13.3 deletion syndrome, which is also known as Phelan-McDermid syndrome. Additional isoforms have been described for this gene but they have not yet been experimentally verified. [provided by RefSeq, Mar 2012]

SHANK3 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0248 (3770/152124) while in subpopulation NFE AF= 0.0377 (2559/67952). AF 95% confidence interval is 0.0364. There are 56 homozygotes in gnomad4. There are 1750 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 3770 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SHANK3	NM_001372044.2	c.1527+50C>T		intron_variant			NP_001358973.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SHANK3	ENST00000262795.7	c.947+48C>T		intron_variant		5		ENSP00000489147.3
SHANK3	ENST00000414786.7	n.1531+48C>T		intron_variant		5
SHANK3	ENST00000673971.2	n.1304+48C>T		intron_variant				ENSP00000501192.2
SHANK3	ENST00000692848.1	c.*48C>T		downstream_gene_variant				ENSP00000510794.2

Frequencies

GnomAD3 genomes AF: 0.0248 AC: 3771 AN: 152006 Hom.: 56 Cov.: 33

Gnomad AFR AF: 0.00996

Gnomad AMI AF: 0.0606

Gnomad AMR AF: 0.0181

Gnomad ASJ AF: 0.0380

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0172

Gnomad FIN AF: 0.0164

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.0377

Gnomad OTH AF: 0.0292

GnomAD3 exomes AF: 0.0202 AC: 2319 AN: 115064 Hom.: 37 AF XY: 0.0208 AC XY: 1251 AN XY: 60256

Gnomad AFR exome AF: 0.00959

Gnomad AMR exome AF: 0.0134

Gnomad ASJ exome AF: 0.0298

Gnomad EAS exome AF: 0.0000979

Gnomad SAS exome AF: 0.0153

Gnomad FIN exome AF: 0.0162

Gnomad NFE exome AF: 0.0315

Gnomad OTH exome AF: 0.0250

GnomAD4 exome AF: 0.0153 AC: 19351 AN: 1264036 Hom.: 307 Cov.: 25 AF XY: 0.0157 AC XY: 9725 AN XY: 618520

Gnomad4 AFR exome AF: 0.00653

Gnomad4 AMR exome AF: 0.0166

Gnomad4 ASJ exome AF: 0.0218

Gnomad4 EAS exome AF: 0.0000289

Gnomad4 SAS exome AF: 0.0129

Gnomad4 FIN exome AF: 0.0145

Gnomad4 NFE exome AF: 0.0159

Gnomad4 OTH exome AF: 0.0181

GnomAD4 genome AF: 0.0248 AC: 3770 AN: 152124 Hom.: 56 Cov.: 33 AF XY: 0.0235 AC XY: 1750 AN XY: 74364

Gnomad4 AFR AF: 0.00993

Gnomad4 AMR AF: 0.0180

Gnomad4 ASJ AF: 0.0380

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0172

Gnomad4 FIN AF: 0.0164

Gnomad4 NFE AF: 0.0377

Gnomad4 OTH AF: 0.0289

Alfa AF: 0.0313 Hom.: 21

Bravo AF: 0.0243

Asia WGS AF: 0.00779 AC: 27 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.20
DANN	Benign	0.39
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs76224556; hg19: chr22-51133524;