chr22-50695096-C-T

Variant names:

• chr22-50695096-C-T
• rs76224556
• ENST00000692848.2:c.1529+48C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The ENST00000692848.2(SHANK3):​c.1529+48C>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 ENST00000692848.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -4.51
• Publications: 11 publications found

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 Gene-Disease associations (from GenCC):

• Phelan-McDermid syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), ClinGen
• schizophrenia 15

  Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 3770 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SHANK3	NM_001372044.2	c.1527+50C>T		intron_variant	Intron 12 of 24		NP_001358973.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SHANK3	ENST00000692848.2	c.1529+48C>T		intron_variant	Intron 11 of 22			ENSP00000510794.2
SHANK3	ENST00000262795.8	c.947+48C>T		intron_variant	Intron 9 of 20	5		ENSP00000489147.3
SHANK3	ENST00000414786.8	n.1531+48C>T		intron_variant	Intron 10 of 21	5
SHANK3	ENST00000673971.3	n.1529+48C>T		intron_variant	Intron 11 of 22			ENSP00000501192.2

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

GnomAD2 exomes AF: 0.0202 AC: 2319 AN: 115064 AF XY: 0.0208

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 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

African (AFR) AF: 0.00653 AC: 184 AN: 28176

American (AMR) AF: 0.0166 AC: 503 AN: 30226

Ashkenazi Jewish (ASJ) AF: 0.0218 AC: 468 AN: 21480

East Asian (EAS) AF: 0.0000289 AC: 1 AN: 34598

South Asian (SAS) AF: 0.0129 AC: 894 AN: 69158

European-Finnish (FIN) AF: 0.0145 AC: 658 AN: 45344

Middle Eastern (MID) AF: 0.0394 AC: 169 AN: 4290

European-Non Finnish (NFE) AF: 0.0159 AC: 15520 AN: 978196

Other (OTH) AF: 0.0181 AC: 954 AN: 52568

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

African (AFR) AF: 0.00993 AC: 412 AN: 41496

American (AMR) AF: 0.0180 AC: 275 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0380 AC: 132 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5180

South Asian (SAS) AF: 0.0172 AC: 83 AN: 4820

European-Finnish (FIN) AF: 0.0164 AC: 174 AN: 10604

Middle Eastern (MID) AF: 0.0612 AC: 18 AN: 294

European-Non Finnish (NFE) AF: 0.0377 AC: 2559 AN: 67952

Other (OTH) AF: 0.0289 AC: 61 AN: 2112

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
PhyloP100		-4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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: rs76224556; hg19: chr22-51133524;