Genetic Variant SHANK1:p.Arg2074Pro (chr19-50662230-C-G) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_016148.5(SHANK1):c.6221G>C(p.Arg2074Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,228 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2074H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Consequence

SHANK1
NM_016148.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.72

Publications

4 publications found

Variant links:

Genes affected

SHANK1 (HGNC:15474): (SH3 and multiple ankyrin repeat domains 1) This gene encodes a member of the SHANK (SH3 domain and ankyrin repeat containing) family of proteins. Members of this family act as scaffold proteins that are required for the development and function of neuronal synapses. Deletions in this gene may be associated with autism spectrum disorder in males. [provided by RefSeq, Apr 2016]

SHANK1 Gene-Disease associations (from GenCC):

autism
Inheritance: AD Classification: STRONG Submitted by: G2P

SHANK1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.37386584).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SHANK1	NM_016148.5 link	c.6221G>C	p.Arg2074Pro	missense_variant	Exon 24 of 24	ENST00000293441.6	NP_057232.2	Q9Y566-1
SHANK1	XM_011527013.3 link	c.6245G>C	p.Arg2082Pro	missense_variant	Exon 25 of 25		XP_011525315.1	H9KV90
SHANK1	XM_011527014.3 link	c.6194G>C	p.Arg2065Pro	missense_variant	Exon 23 of 23		XP_011525316.1	Q9Y566-3
SHANK1	XM_047438894.1 link	c.4394G>C	p.Arg1465Pro	missense_variant	Exon 10 of 10		XP_047294850.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SHANK1	ENST00000293441.6 link	c.6221G>C	p.Arg2074Pro	missense_variant	Exon 24 of 24	1	NM_016148.5	ENSP00000293441.1		Q9Y566-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152228

Hom.:

Cov.:

show subpopulations

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152228

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74368

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41460

American (AMR)

AF:

0.00

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68040

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.675

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.43

BayesDel_addAF

Benign

-0.017

BayesDel_noAF

Benign

-0.26

CADD

Uncertain

(source)

DANN

Benign

0.93

DEOGEN2

Uncertain

0.43

.;T;.;.

Eigen

Uncertain

0.25

Eigen_PC

Benign

0.22

FATHMM_MKL

Benign

0.73

LIST_S2

Uncertain

0.88

D;D;D;D

M_CAP

Uncertain

0.17

MetaRNN

Benign

0.37

T;T;T;T

MetaSVM

Benign

-0.84

MutationAssessor

Benign

1.7

.;L;.;.

PhyloP100

1.7

PrimateAI

Pathogenic

0.84

PROVEAN

Pathogenic

-5.0

D;D;D;D

REVEL

Benign

0.22

Sift

Uncertain

0.0010

D;D;D;D

Sift4G

Benign

0.095

T;D;D;D

Polyphen

1.0

D;D;.;.

Vest4

0.50

MutPred

0.16

.;Gain of glycosylation at R2074 (P = 0.0108);.;.;

MVP

0.50

MPC

0.97

ClinPred

0.98

GERP RS

3.5

Varity_R

0.66

gMVP

0.51

Mutation Taster

=75/25

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over