dbSNP rs375851821: SIPA1L2:p.Gly1637Ala (chr1-232403478-C-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_020808.5(SIPA1L2):c.4910G>C(p.Gly1637Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,698 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict 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. G1637D) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

SIPA1L2
NM_020808.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.938

Publications

0 publications found

Variant links:

Genes affected

SIPA1L2 (HGNC:23800): (signal induced proliferation associated 1 like 2) This gene encodes a member of the signal-induced proliferation-associated 1 like family. Members of this family contain a GTPase activating domain, a PDZ domain and a C-terminal coiled-coil domain with a leucine zipper. A similar protein in rat acts as a GTPases for the small GTPase Rap. [provided by RefSeq, Sep 2015]

SIPA1L2 links:

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ACMG classification

Classification was made for transcript

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=0.024921328).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020808.5. 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
	SIPA1L2	NM_020808.5	MANE Select	c.4910G>C	p.Gly1637Ala	missense	Exon 21 of 23	NP_065859.3	Q9P2F8-1
	SIPA1L2	NM_001377488.1		c.4856G>C	p.Gly1619Ala	missense	Exon 20 of 22	NP_001364417.1	A0A6Q8PH54

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SIPA1L2	ENST00000674635.1	MANE Select	c.4910G>C	p.Gly1637Ala	missense	Exon 21 of 23	ENSP00000502693.1	Q9P2F8-1
SIPA1L2	ENST00000676213.1		c.5063G>C	p.Gly1688Ala	missense	Exon 21 of 23	ENSP00000501897.1	A0A6Q8PFQ0
SIPA1L2	ENST00000964479.1		c.5063G>C	p.Gly1688Ala	missense	Exon 22 of 24	ENSP00000634538.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461698

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727154

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33476

American (AMR)

AF:

0.00

AC:

AN:

44708

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26122

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.00

AC:

AN:

86230

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53412

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111910

Other (OTH)

AF:

0.00

AC:

AN:

60376

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.061

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.69

CADD

Benign

(source)

DANN

Benign

0.16

DEOGEN2

Benign

0.0097

Eigen

Benign

-1.0

Eigen_PC

Benign

-0.90

FATHMM_MKL

Benign

0.20

LIST_S2

Benign

0.68

M_CAP

Benign

0.0056

MetaRNN

Benign

0.025

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.22

PhyloP100

0.94

PrimateAI

Benign

0.32

PROVEAN

Benign

1.4

REVEL

Benign

0.049

Sift

Benign

0.72

Sift4G

Benign

0.64

Polyphen

0.0

Vest4

0.052

MutPred

0.17

Loss of disorder (P = 0.1016)

MVP

0.068

MPC

0.19

ClinPred

0.015

GERP RS

0.59

Varity_R

0.029

gMVP

0.10

Mutation Taster

=98/2

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over