16-84849457-C-A

Position:

• chr16-84849457-C-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_031476.4(CRISPLD2):​c.432C>A​(p.Ser144Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00549 in 1,614,136 control chromosomes in the GnomAD database, including 37 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0033 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0057 (36 hom.)
• Consequence: CRISPLD2 NM_031476.4 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.50

Genes affected

CRISPLD2 (HGNC:25248): (cysteine rich secretory protein LCCL domain containing 2) Predicted to enable glycosaminoglycan binding activity. Involved in face morphogenesis. Located in transport vesicle. [provided by Alliance of Genome Resources, Apr 2022]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0067970753).
• BP6: Variant 16-84849457-C-A is Benign according to our data. Variant chr16-84849457-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 710712.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 36 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CRISPLD2	NM_031476.4	c.432C>A	p.Ser144Arg	missense_variant	4/15	ENST00000262424.10	NP_113664.1
CRISPLD2	XM_005256190.2	c.432C>A	p.Ser144Arg	missense_variant	5/16		XP_005256247.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CRISPLD2	ENST00000262424.10	c.432C>A	p.Ser144Arg	missense_variant	4/15	1	NM_031476.4	ENSP00000262424	P4
	ENST00000648152.1	n.373-623G>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.00332 AC: 506 AN: 152192 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00128

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00170

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00373

Gnomad FIN AF: 0.000659

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00573

Gnomad OTH AF: 0.00431

GnomAD3 exomes AF: 0.00364 AC: 916 AN: 251378 Hom.: 3 AF XY: 0.00383 AC XY: 520 AN XY: 135882

Gnomad AFR exome AF: 0.000615

Gnomad AMR exome AF: 0.00231

Gnomad ASJ exome AF: 0.000993

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00444

Gnomad FIN exome AF: 0.00102

Gnomad NFE exome AF: 0.00554

Gnomad OTH exome AF: 0.00456

GnomAD4 exome AF: 0.00572 AC: 8357 AN: 1461826 Hom.: 36 Cov.: 42 AF XY: 0.00569 AC XY: 4141 AN XY: 727214

Gnomad4 AFR exome AF: 0.00102

Gnomad4 AMR exome AF: 0.00226

Gnomad4 ASJ exome AF: 0.000765

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00458

Gnomad4 FIN exome AF: 0.000768

Gnomad4 NFE exome AF: 0.00672

Gnomad4 OTH exome AF: 0.00477

GnomAD4 genome AF: 0.00332 AC: 505 AN: 152310 Hom.: 1 Cov.: 33 AF XY: 0.00316 AC XY: 235 AN XY: 74476

Gnomad4 AFR AF: 0.00128

Gnomad4 AMR AF: 0.00170

Gnomad4 ASJ AF: 0.000865

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00352

Gnomad4 FIN AF: 0.000659

Gnomad4 NFE AF: 0.00573

Gnomad4 OTH AF: 0.00426

Alfa AF: 0.00472 Hom.: 1

Bravo AF: 0.00322

TwinsUK AF: 0.00243 AC: 9

ALSPAC AF: 0.00493 AC: 19

ESP6500AA AF: 0.00114 AC: 5

ESP6500EA AF: 0.00547 AC: 47

ExAC AF: 0.00384 AC: 466

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00600

EpiControl AF: 0.00516

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 21, 2018	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

CRISPLD2-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 19, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	12
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0034	T;T;.
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.48
FATHMM_MKL	Benign	0.19	N
LIST_S2	Uncertain	0.89	D;D;D
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.0068	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.14	N;.;N
MutationTaster	Benign	0.94	N;N;N
PrimateAI	Benign	0.44	T
PROVEAN	Benign	1.6	N;N;N
REVEL	Benign	0.033
Sift	Benign	0.14	T;T;T
Sift4G	Benign	0.25	T;T;T
Polyphen		0.0050	B;.;B
Vest4		0.30
MutPred		0.46		Loss of glycosylation at S144 (P = 0.0677);Loss of glycosylation at S144 (P = 0.0677);Loss of glycosylation at S144 (P = 0.0677);
MVP		0.49
MPC		0.084
ClinPred		0.032	T
GERP RS		2.5
Varity_R		0.062
gMVP		0.73

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

LitVar

Other links and lift over

dbSNP: rs138500867; hg19: chr16-84883063;