chr22-50674678-G-C

Variant names:

• chr22-50674678-G-C
• rs1196868406
• NM_001372044.2:c.262G>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Moderate BP6_Moderate

The NM_001372044.2(SHANK3):​c.262G>C​(p.Val88Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000275 in 1,091,796 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 10/15 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0000069 (0 hom., cov: 29)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: SHANK3 NM_001372044.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.674
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.072030276).
• BP6: Variant 22-50674678-G-C is Benign according to our data. Variant chr22-50674678-G-C is described in ClinVar as Likely_benign. ClinVar VariationId is 1197277.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001372044.2. 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.262G>C	p.Val88Leu	missense	Exon 3 of 25	NP_001358973.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SHANK3	ENST00000692848.2		c.262G>C	p.Val88Leu	missense	Exon 2 of 23	ENSP00000510794.2	A0A8I5KZC4
	SHANK3	ENST00000414786.8	TSL:5	n.264G>C		non_coding_transcript_exon	Exon 1 of 22
	SHANK3	ENST00000673971.3		n.262G>C		non_coding_transcript_exon	Exon 2 of 23	ENSP00000501192.2	A0A669KBA8

Frequencies

GnomAD3 genomes AF: 0.00000693 AC: 1 AN: 144340 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000154

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000211 AC: 2 AN: 947456 Hom.: 0 Cov.: 29 AF XY: 0.00000220 AC XY: 1 AN XY: 454612

African (AFR) AF: 0.00 AC: 0 AN: 18080

American (AMR) AF: 0.00 AC: 0 AN: 12108

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 10030

East Asian (EAS) AF: 0.00 AC: 0 AN: 5916

South Asian (SAS) AF: 0.00 AC: 0 AN: 38114

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6978

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2084

European-Non Finnish (NFE) AF: 0.00000243 AC: 2 AN: 821870

Other (OTH) AF: 0.00 AC: 0 AN: 32276

GnomAD4 genome AF: 0.00000693 AC: 1 AN: 144340 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 70184

African (AFR) AF: 0.00 AC: 0 AN: 40082

American (AMR) AF: 0.00 AC: 0 AN: 14678

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3374

East Asian (EAS) AF: 0.00 AC: 0 AN: 4776

South Asian (SAS) AF: 0.00 AC: 0 AN: 4714

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8466

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 286

European-Non Finnish (NFE) AF: 0.0000154 AC: 1 AN: 65096

Other (OTH) AF: 0.00 AC: 0 AN: 1990

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

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
AlphaMissense	Pathogenic	0.69
BayesDel_noAF	Benign	-0.35
CADD	Benign	17
DANN	Benign	0.96
DEOGEN2	Benign	0.020	T
Eigen	Benign	-0.78
Eigen_PC	Benign	-0.82
FATHMM_MKL	Benign	0.11	N
LIST_S2	Uncertain	0.89	D
M_CAP	Pathogenic	0.34	D
MetaRNN	Benign	0.072	T
MetaSVM	Benign	-1.0	T
PhyloP100		-0.67
PrimateAI	Pathogenic	0.88	D
REVEL	Benign	0.012
Sift4G	Uncertain	0.017	D
Vest4		0.13
MutPred		0.37		Gain of sheet (P = 0.1945)
GERP RS		-0.43
PromoterAI		0.0019	Neutral
gMVP		0.32
Mutation Taster		=92/8	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1196868406; hg19: chr22-51113106;