ENST00000692848:c.-158G>T

Variant names:

• chr22-50674484-G-T
• rs1185730781
• NM_001372044.2:c.70G>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The ENST00000692848.2(SHANK3):​c.70G>T​(p.Ala24Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000296 in 141,890 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 4/4 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00030 (0 hom., cov: 21)
  • Exomes 𝑓: 0.00015 (0 hom.)
• Consequence: SHANK3 ENST00000692848.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.881
• Publications: 0 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: ClinGen, G2P, Labcorp Genetics (formerly Invitae), PanelApp Australia, Ambry Genetics, Laboratory for Molecular Medicine
• schizophrenia 15

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

ENSG00000301328 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63).
• BP6: Variant 22-50674484-G-T is Benign according to our data. Variant chr22-50674484-G-T is described in ClinVar as Likely_benign. ClinVar VariationId is 3250871.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000304 (41/135060) while in subpopulation AFR AF = 0.00105 (39/37104). AF 95% confidence interval is 0.00079. There are 0 homozygotes in GnomAd4. There are 17 alleles in the male GnomAd4 subpopulation. Median coverage is 21. This position passed quality control check.
• BS2: High AC in GnomAd4 at 41 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000692848.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SHANK3	NM_001372044.2	MANE Select	c.70G>T	p.Ala24Ser	missense	Exon 2 of 25	NP_001358973.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SHANK3	ENST00000692848.2		c.70G>T	p.Ala24Ser	missense	Exon 1 of 23	ENSP00000510794.2	A0A8I5KZC4
	SHANK3	ENST00000414786.8	TSL:5	n.70G>T		non_coding_transcript_exon	Exon 1 of 22
	SHANK3	ENST00000673971.3		n.70G>T		non_coding_transcript_exon	Exon 1 of 23	ENSP00000501192.2	A0A669KBA8

Frequencies

GnomAD3 genomes AF: 0.000304 AC: 41 AN: 134994 Hom.: 0 Cov.: 21

Gnomad AFR AF: 0.00105

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000719

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000161

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000146 AC: 1 AN: 6830 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 3378

African (AFR) AF: 0.0125 AC: 1 AN: 80

American (AMR) AF: 0.00 AC: 0 AN: 6

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 40

East Asian (EAS) AF: 0.00 AC: 0 AN: 26

South Asian (SAS) AF: 0.00 AC: 0 AN: 904

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 8

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 5594

Other (OTH) AF: 0.00 AC: 0 AN: 170

GnomAD4 genome AF: 0.000304 AC: 41 AN: 135060 Hom.: 0 Cov.: 21 AF XY: 0.000259 AC XY: 17 AN XY: 65584

African (AFR) AF: 0.00105 AC: 39 AN: 37104

American (AMR) AF: 0.0000718 AC: 1 AN: 13924

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3274

East Asian (EAS) AF: 0.00 AC: 0 AN: 4280

South Asian (SAS) AF: 0.00 AC: 0 AN: 4086

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 7454

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 230

European-Non Finnish (NFE) AF: 0.0000161 AC: 1 AN: 62008

Other (OTH) AF: 0.00 AC: 0 AN: 1900

Alfa AF: 0.000498 Hom.: 0

Bravo AF: 0.000495

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	17
DANN	Benign	0.84
PhyloP100		0.88
PromoterAI		0.017	Neutral
Mutation Taster		=300/0	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1185730781; hg19: chr22-51112912;