chr1-222522679-C-T

Variant names:

• chr1-222522679-C-T
• rs4846759
• NM_024746.4:c.2097G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_024746.4(HHIPL2):​c.2097G>A​(p.Arg699Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00221 in 1,614,218 control chromosomes in the GnomAD database, including 101 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0034 (10 hom., cov: 32)
  • Exomes 𝑓: 0.0021 (91 hom.)
• Consequence: HHIPL2 NM_024746.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.248
• Publications: 1 publications found

Genes affected

HHIPL2 (HGNC:25842): (HHIP like 2) Predicted to enable catalytic activity. Predicted to be located in extracellular region. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP6: Variant 1-222522679-C-T is Benign according to our data. Variant chr1-222522679-C-T is described in ClinVar as Benign. ClinVar VariationId is 776341.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.248 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00339 (517/152324) while in subpopulation AMR AF = 0.0236 (361/15294). AF 95% confidence interval is 0.0216. There are 10 homozygotes in GnomAd4. There are 284 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 10 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024746.4. 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
	HHIPL2	NM_024746.4	MANE Select	c.2097G>A	p.Arg699Arg	synonymous	Exon 9 of 9	NP_079022.2	Q6UWX4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HHIPL2	ENST00000343410.7	TSL:1 MANE Select	c.2097G>A	p.Arg699Arg	synonymous	Exon 9 of 9	ENSP00000342118.6	Q6UWX4
	HHIPL2	ENST00000473144.5	TSL:3	n.759G>A		non_coding_transcript_exon	Exon 4 of 4
	HHIPL2	ENST00000468172.1	TSL:1	n.*130G>A		downstream_gene	N/A

Frequencies

GnomAD3 genomes AF: 0.00339 AC: 516 AN: 152206 Hom.: 10 Cov.: 32

Gnomad AFR AF: 0.000651

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0236

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0150

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000441

Gnomad OTH AF: 0.00623

GnomAD2 exomes AF: 0.00838 AC: 2106 AN: 251266 AF XY: 0.00641

Gnomad AFR exome AF: 0.000431

Gnomad AMR exome AF: 0.0516

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0134

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000969

Gnomad OTH exome AF: 0.00718

GnomAD4 exome AF: 0.00209 AC: 3058 AN: 1461894 Hom.: 91 Cov.: 31 AF XY: 0.00186 AC XY: 1350 AN XY: 727248

African (AFR) AF: 0.000239 AC: 8 AN: 33480

American (AMR) AF: 0.0492 AC: 2200 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0153 AC: 609 AN: 39700

South Asian (SAS) AF: 0.000499 AC: 43 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.0000791 AC: 88 AN: 1112012

Other (OTH) AF: 0.00180 AC: 109 AN: 60396

GnomAD4 genome AF: 0.00339 AC: 517 AN: 152324 Hom.: 10 Cov.: 32 AF XY: 0.00381 AC XY: 284 AN XY: 74484

African (AFR) AF: 0.000649 AC: 27 AN: 41582

American (AMR) AF: 0.0236 AC: 361 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.0150 AC: 78 AN: 5184

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000441 AC: 30 AN: 68020

Other (OTH) AF: 0.00616 AC: 13 AN: 2110

Alfa AF: 0.00115 Hom.: 2

Bravo AF: 0.00600

Asia WGS AF: 0.00808 AC: 28 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	2.3
DANN	Benign	0.48
PhyloP100		0.25
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4846759; hg19: chr1-222696021; COSMIC: COSV100596664; COSMIC: COSV100596664;